Histotripsy systems and methods

ABSTRACT

A histotripsy therapy system configured for the treatment of tissue is provided, which may include any number of features. Provided herein are systems and methods that provide efficacious non-invasive and minimally invasive therapeutic, diagnostic and research procedures. In particular, provided herein are optimized systems and methods that provide targeted, efficacious histotripsy in a variety of different regions and under a variety of different conditions without causing undesired tissue damage to intervening/non-target tissues or structures.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/698,587, filed Nov. 27, 2019, which claims the benefit of U.S.Provisional Patent Application No. 62/772,473, filed Nov. 28, 2018,titled “HISTOTRIPSY SYSTEMS AND METHODS”, which is incorporated byreference in its entirety.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

FIELD

The present disclosure details novel histotripsy systems configured toproduce acoustic cavitation, methods, devices and procedures for theminimally and non-invasive treatment of healthy, diseased and/or injuredtissue. The histotripsy systems and methods described herein, alsoreferred to Histotripsy, may include transducers, drive electronics,positioning robotics, imaging systems, and integrated treatment planningand control software to provide comprehensive treatment and therapy forsoft tissues in a patient.

BACKGROUND

Many medical conditions require invasive surgical interventions.Invasive procedures often involve incisions, trauma to muscles, nervesand tissues, bleeding, scarring, trauma to organs, pain, need fornarcotics during and following procedures, hospital stays, and risks ofinfection. Non-invasive and minimally invasive procedures are oftenfavored, if available, to avoid or reduce such issues. Unfortunately,non-invasive and minimally invasive procedures may lack the precision,efficacy or safety required for treatment of many types of diseases andconditions. Enhanced non-invasive and minimally invasive procedures areneeded, preferably not requiring ionizing or thermal energy fortherapeutic effect.

Histotripsy, or pulsed ultrasound cavitation therapy, is a technologywhere extremely short, intense bursts of acoustic energy inducecontrolled cavitation (microbubble formation) within the focal volume.The vigorous expansion and collapse of these microbubbles mechanicallyhomogenizes cells and tissue structures within the focal volume. This isa very different end result than the coagulative necrosis characteristicof thermal ablation. To operate within a non-thermal, Histotripsy realm;it is necessary to deliver acoustic energy in the form of high amplitudeacoustic pulses with low duty cycle.

Compared with conventional focused ultrasound technologies, Histotripsyhas important advantages: 1) the destructive process at the focus ismechanical, not thermal; 2) cavitation appears bright on ultrasoundimaging thereby confirming correct targeting and localization oftreatment; 3) treated tissue generally, but not always, appears darker(more hypoechoic) on ultrasound imaging, so that the operator knows whathas been treated; and 4) Histotripsy produces lesions in a controlledand precise manner. It is important to emphasize that unlike thermalablative technologies such as microwave, radiofrequency, andhigh-intensity focused ultrasound (HIFU), Histotripsy relies on themechanical action of cavitation for tissue destruction.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe claims that follow. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIGS. 1A-1B illustrate an ultrasound imaging and therapy system.

FIG. 2 provides a schematic diagram of an inductive driver circuitconfigured to excite ultrasound transducers for histotripsy therapy.

FIG. 3 illustrates a schematic diagram of an autotransforming inductivedriver circuit including an inductor Lx with a center tap that solvesthe shortcomings of the inductive driver circuit of FIG. 2 .

FIG. 4 illustrates a schematic diagram of an autotransforming inductivedriver with another active or passive electronic component.

FIG. 5 illustrates a schematic diagram of an autotransforming inductivedriver with a protective circuit.

FIG. 6 illustrates another schematic diagram of an autotransforminginductive driver with a protective circuit.

FIGS. 7A and 7B illustrate one example of a treatment pattern forablating a target tissue volume.

FIGS. 8-9 illustrate examples of a column shaped bubble cloud.

FIG. 10 illustrates an example of a rectilinear treatment pattern.

FIGS. 11A, 11B, 11C, 11D, and 11E illustrate examples of a radialtreatment pattern.

FIG. 12 is an illustration of one example of using seven test pulselocations within a spherical treatment volume.

FIGS. 13A-13B illustrate temperature profiles resulting from sixdifferent histotripsy pulse schemes.

FIGS. 14A-14B illustrate temperature profiles resulting from threedifferent histotripsy pulse schemes.

FIGS. 15A-15B illustrate the thermal profiles resulting from the fivetreatment schemes used to investigate the implementation of coolingsteps during volume treatment.

FIGS. 16A-16B illustrate the thermal effect of high-PRF sequences withcooling times.

FIGS. 17A-17E illustrate examples of a graphical user interface of thesystem.

SUMMARY OF THE DISCLOSURE

Histotripsy produces tissue fractionation through dense energetic bubbleclouds generated by short, high-pressure, ultrasound pulses. When usingpulses shorter than 2 cycles, the generation of these energetic bubbleclouds only depends on where the peak negative pressure (P−) exceeds anintrinsic threshold for inducing cavitation in a medium (typically 26-30MPa in soft tissue with high water content).

A method of treating tissue is provided, comprising the steps oftransmitting ultrasound pulses into a first test location with at leastone ultrasound transducer, determining a first cavitation threshold atthe first test location, transmitting ultrasound pulses into a secondtest location with the at least one ultrasound transducer, determining asecond cavitation threshold at the second test location, adjusting afirst driving voltage and/or PRF of the at least one transducer based onthe first cavitation threshold, transmitting ultrasound pulses into thefirst test location with the at least one ultrasound transducer at thefirst adjusted driving voltage and/or PRF to generate cavitation at thefirst test location, adjusting a second driving voltage and/or PRF ofthe at least one transducer based on the second cavitation threshold andtransmitting ultrasound pulses into the second test location with the atleast one ultrasound transducer at the second adjusted driving voltageand/or PRF to generate cavitation at the second test location.

In some embodiments, the method further comprises repeating the steps atthree or more test locations in the tissue.

In other embodiments, the method further comprises repeating the stepsat six or more test locations in the tissue. The six or more testlocations may be positioned in cubic coordinates around a center of saidtarget location.

In some embodiments, the method further comprises repeating the steps atseven or more test locations in the tissue. Six target locations may bepositioned in cubic coordinates spaced around a central test location.

In some embodiments, the method further comprises determining acavitation threshold for a third test location located between the firstand second test locations by extrapolating a cavitation threshold basedon the cavitation thresholds of the first and second test locations.

In other embodiments, the method further comprises interpolatingrequired drive amplitudes for the first test location, the second testlocation, and the third test location to ensure that each of thecavitation thresholds is achieved. he first and second test locationsmay be positioned near an outer boundary of the tissue.

In some embodiments, the tissue comprises a tumor volume. In otherembodiments, the tissue comprises a tumor volume and a margin around thetumor volume.

In some embodiments, the first and second test locations are two or moretumors.

In some embodiments, the method further comprises positioning the firstand second test locations on the tissue in a graphical user interface.

In some embodiments, the steps are performed automatically withoutintervention by a user.

In some embodiments, the method further comprises making a depthmeasurement at the first and second test locations.

In other embodiments, the method further comprises determining a maximumamount of energy that may be applied to the first test location withoutgenerating undesired damage to the first test location or surroundingintervening tissue.

In some embodiments, the method further comprises determining athreshold of energy that may be applied to the first location withoutgenerating undesired damage to the first test location or surroundingintervening tissue.

In alternative embodiments, the method further comprises positioning theat least one transducer 3 cm or more from the tissue.

In some embodiments, the method further comprises positioning the atleast one transducer 5 cm or more from the tissue.

In other embodiments, the method further comprises positioning the atleast one transducer 10 cm or more from the tissue.

In some embodiments, one or more bone structures are located between theat least one transducer and tissue.

In some examples, the ultrasound pulses comprise histotripsy pulses.

A method of treating tissue with a pulse repetition frequency (PRF) of400 Hz or greater to generate acoustic cavitation is provided,comprising the steps of transmitting ultrasound pulses into a first testlocation with at least one ultrasound transducer, determining a firstcavitation threshold at the first test location, transmitting ultrasoundpulses into a second test location with the at least one ultrasoundtransducer, determining a second cavitation threshold at the second testlocation, adjusting a first driving voltage and/or pulse repetitionfrequency of the at least one transducer based on the first cavitationthreshold, transmitting ultrasound pulses into the first test locationwith the at least one ultrasound transducer at the first adjusteddriving voltage to generate cavitation at the first test location,adjusting a second driving voltage and/or pulse repetition frequency ofthe at least one transducer based on the second cavitation threshold,and transmitting ultrasound pulses into the second test location withthe at least one ultrasound transducer at the second adjusted drivingvoltage to generate cavitation at the second test location.

In some examples, the PRF is between 400 to 900 Hz, between 600 to 900Hz, between 500 to 700 Hz, or the PRF is 600 Hz.

In some embodiments, the method further comprises implementing a testprotocol that identifies treatment power thresholds at two or more testlocations in the tissue.

In some embodiments, the method further comprises implementing atreatment protocol that selects a power of one or more treatmentlocations within the tissue based on the test protocol.

In other embodiments, the method further comprises transmitting theultrasound pulses with a robot.

In some embodiments, the method further comprises destroying cells in atarget tissue with the transmitted pulses. In additional embodiments,the method further comprises destroying cells in a target tissue withoutdamaging critical tissue structures. The critical tissue structures maybe selected from the group consisting of blood vessels, bile ducts,collecting systems, organ capsules and visceral structures.

A method of treating tissue with ultrasound energy is provided,comprising the steps of delivering ultrasound pulses into a targettissue with one or more ultrasound transducers to generate acousticcavitation in the target tissue, adjusting a power and a position of theone or more ultrasound transducers to generate bubble clouds at aplurality of different locations in the target tissue over a pluralityof time periods to treat at least two locations located innon-contiguous regions of the target tissue in sequential time periods.

In some embodiments, the method further comprises forming a plurality oftreatment lines that span the target tissue. In some examples, theplurality of treatment lines comprises a first line that spans from afirst side of the target tissue to a second side of the target tissue.In other examples, the plurality of treatment lines further proceedsalong a second line from the first side of said target tissue to thesecond side of the target tissue.

In some embodiments, the plurality of treatment lines further proceedsalong third and subsequent lines, each starting from the first side ofthe target tissue to the second side of the target tissue.

In some embodiments, the first side comprises a top region of the targettissue located closest to the one or more ultrasound transducers and thesecond side comprises a bottom region of the target tissue located mostdistal to the one or more ultrasound transducers.

In some embodiments, the method further comprises identifying treatmentpower thresholds at two or more test locations in said target tissue.

In some embodiments, the method further comprises adjusting a powerlevel of the one or more transducers based on the treatment powerthresholds.

In other embodiments, the method further comprises performing a depthmeasurement at the two or more test locations.

In some embodiments, the method further comprises positioning the one ormore ultrasound transducers with a robotic arm with three or moredegrees of freedom.

In additional embodiments, the method further comprises positioning theone or more ultrasound transducers with a robotic arm wherein three ormore degrees of freedom is six degrees of freedom.

In some embodiments, the method further comprises displaying real-timevisualization of the bubble cloud at first and subsequent locations inthe treatment pattern during the treatments.

In other embodiments, the method further comprises displaying a statusof the treatment and position of the bubble cloud in the plannedtreatment pattern, wherein status includes information derived from alocation, position, percentage of treatment completion, percentage oftreatment remaining, and time. In some embodiments, this can includedisplaying a combination of real-time visualization and CT and/or MRIimages.

A system is provided, comprising one or more ultrasound transducersconfigured to generate acoustic cavitation in a tissue at a targetlocation, and one or more computer processors configured to controlpower and position of said ultrasound transducers, wherein said one ormore processors are configured to implement a treatment pattern in theone or more ultrasound transducers that generates bubble clouds at aplurality of different locations in the target tissue over a pluralityof time periods, wherein at least two of said locations are treated insequential time periods are located in contiguous columns of the targettissue.

In some embodiments, the treatment pattern comprises a plurality oftreatment columns that span said target location.

In other embodiments, the treatment pattern proceeds along a firstcolumn location to said starting position of a second column location.

In some examples, the treatment pattern further proceeds along a secondcolumn from said first column location within said target location to athird column starting position within said target location.

In other embodiments, the treatment pattern further proceeds along thirdand subsequent columns of said target location.

In some embodiments, the treatment pattern comprises a radial spiralpattern. The radial spiral pattern can be formed from the innerlocations to outer locations.

In some embodiments, the one or more processors are further configuredto run implement a test protocol that identifies treatment powerthresholds at two or more test locations in said target location. Powerapplied in said treatment pattern can be selected using informationobtained from said test protocol. The test protocol can further includea depth measurement.

In some examples, the system is configured to dynamically controltreatment parameters at a plurality of treatment locations in the targettissue. In other embodiments, the system is further configured tocomprise a robotic arm with three or more degrees of freedom to controlposition of said one or more transducers. Additionally, the system canbe further configured to comprise a robotic arm wherein three or moredegrees of freedom is six degrees of freedom to control position of saidone or more transducers.

The system can be further configured to display real-time visualizationof the bubble cloud at first and subsequent locations in the treatmentpattern during the treatment, as displayed to the user in one or moresystem user interfaces.

In some embodiments, the system is configured to display the status ofthe treatment and position of the bubble cloud in the planned treatmentpattern, wherein status includes information derived from a listincluding location, position, percentage of treatment completion,percentage of treatment remaining, and time.

A system is provided, comprising one or more ultrasound transducersconfigured to generate acoustic cavitation in a tissue at a targetlocation, and one or more computer processors configured to controlpower and position of said ultrasound transducers, wherein the one ormore processors are configured to adjust energy delivery from the one ormore ultrasound transducers based on treatment specific parametersaccounting for tissue variation in the target location and/orobstructions located between the transducers and the target location.

The energy adjustment can comprise a timing of energy delivery, or anamplitude of energy delivery, or a selection of a cooling time period.

In some examples, the timing of energy delivery comprises application ofenergy for a first time period at a first location in the target tissueand for a second, different time period at a second location in thetarget tissue. Alternatively, the timing of energy delivery comprisesapplication of energy for a first amplitude at a first location in thetarget tissue and for a second, different amplitude at a second locationin the target tissue. In some examples, the timing of energy deliverycomprises application of energy for a third or more time period, at acorresponding third or more location, in the target tissue.

In one embodiment, the amplitude of energy delivery comprisesapplication of energy for a third or more amplitude, at a correspondingthird or more location, in the target tissue.

In some examples, the system comprises one or more user interfaces forreceiving user provided input of said treatment specific parameters.

In one embodiment, treatment specific parameters are pulled from alook-up table that contains energy delivery information indexed againsta target tissue depth. The target tissue depth can be determined basedon a distance between the center of the target tissue and a body walllocated between the target tissue and the said one or more transducers.In some embodiments, the look-up table is specific for said one or moretransducers. In other embodiments, the look-up table is specific forsaid target tissue type.

A method of treating a target tissue with ultrasound energy is alsoprovided, wherein the target tissue comprises a first tissue componentand a second tissue component, the method comprising the steps ofdelivering ultrasound pulses into the target tissue to form cavitationin the first tissue component but not the second tissue component.

An autotransforming inductive driver configured to excite ultrasoundtransducers is also provided, comprising an IGBT transistor, anoscillating circuit configured to temporarily store energy in a magneticfield when the IGBT transistor is excited with a single pulse, whereinthe oscillating circuit includes an inductor with a tap that ispositioned along a length of the inductor to increase a voltagegenerated across the inductor.

A method of treating a target tissue volume with an ultrasound system,comprising determining a depth of the target tissue volume, determininga total treatment time, positioning a focus of the ultrasound system onthe target tissue volume, selecting a drive voltage, for the selecteddrive voltage, automatically determining in the ultrasound system afirst percentage of the total treatment time for which ultrasound pulsesare to be delivered to the target tissue volume and a second percentageof the total treatment time for which no ultrasound pulses are to bedelivered to the target tissue volume, and initiating a pulse sequencein the ultrasound system configured to deliver ultrasound pulses to thetarget tissue for the first percentage of the total treatment time.

In some examples, determining the first percentage and the secondpercentage further comprises using a lookup table based on the drivevoltage and the depth.

In one embodiment, the drive voltage and the depth of the target tissuevolume are used to determine the first percentage and the secondpercentage.

In some embodiments, the lookup table provides a cooling coefficientused to determine a ratio between the first percentage and the secondpercentage.

In some examples, the first percentage comprises 50% and the secondpercentage comprises 50%, the first percentage comprises 33% and thesecond percentage comprises 67%, the first percentage comprises 25% andthe second percentage comprises 75%, the first percentage comprises 20%and the second percentage comprises 80%, the first percentage comprises16% and the second percentage comprises 84%.

In one embodiment, delivering the ultrasound pulses to the target tissuefor the first percentage of the total treatment time prevents unwanteddamage to surrounding tissues.

DETAILED DESCRIPTION

Provided herein are systems and methods that provide efficaciousnon-invasive and minimally invasive therapeutic, diagnostic and researchprocedures. In particular, provided herein are optimized systems andmethods that provide targeted, efficacious histotripsy in a variety ofdifferent regions and under a variety of different conditions withoutcausing undesired tissue damage to intervening/non-target tissues orstructures.

Balancing desired tissue destruction in target regions with theavoidance of damage to non-target regions presents a technicalchallenge. This is particularly the case where time efficient proceduresare desired. Conditions that provide fast, efficacious tissuedestruction tend to cause undue heating in non-target tissues. Underheating can be avoided by reducing energy or slower delivery of energy,both of which run contrary to the goals of providing a fast andefficacious destruction of target tissue. Provided herein are a numberof technologies that individually and collectively allow for fast,efficacious target treatment without undesired damage to non-targetregions.

The system, methods and devices of the disclosure may be used for theminimally or non-invasive acoustic cavitation and treatment of healthy,diseased and/or injured tissue, including in extracorporeal,percutaneous, endoscopic, laparoscopic, and/or as integrated into arobotically-enabled medical system and procedures. As will be describedbelow, the histotripsy system may include various electrical, mechanicaland software sub-systems, including a Cart, Therapy, Integrated Imaging,Robotics, Coupling and Software. The system also may comprise variousOther Components, Ancillaries and Accessories, including but not limitedto patient surfaces, tables or beds, computers, cables and connectors,networking devices, power supplies, displays, drawers/storage, doors,wheels, illumination and lighting and various simulation and trainingtools, etc. All systems, methods and meanscreating/controlling/delivering histotripsy are considered to be a partof this disclosure, including new related inventions disclosed herein.

In one embodiment, the histotripsy system is configured as a mobiletherapy cart, which further includes a touchscreen display with anintegrated control panel with a set of physical controls, a robotic arm,a therapy head positioned on the distal end of the robot, a patientcoupling system and software to operate and control the system.

The mobile therapy cart architecture can comprise internal components,housed in a standard rack mount frame, including a histotripsy therapygenerator, high voltage power supply, transformer, power distribution,robot controller, computer, router and modem, and an ultrasound imagingengine. The front system interface panel can comprise input/outputlocations for connectors, including those specifically for twoultrasound imaging probes (handheld and probe coaxially mounted in thetherapy transducer), a histotripsy therapy transducer, AC power andcircuit breaker switches, network connections and a foot pedal. The rearpanel of the cart can comprise air inlet vents to direct airflow to airexhaust vents located in the side, top and bottom panels. The sidepanels of the cart include a holster and support mechanism for holdingthe handheld imaging probe. The base of the cart can be comprised of acast base interfacing with the rack mounted electronics and providing aninterface to the side panels and top cover. The base also includes fourrecessed casters with a single total locking mechanism. The top cover ofthe therapy cart can comprise the robot arm base and interface, and acircumferential handle that follows the contour of the cart body. Thecart can have inner mounting features that allow technician access tocart components through access panels.

The touchscreen display and control panel may include user inputfeatures including physical controls in the form of six dials, a spacemouse and touchpad, an indicator light bar, and an emergency stop,together configured to control imaging and therapy parameters, and therobot. The touchscreen support arm is configured to allow standing andseated positions, and adjustment of the touchscreen orientation andviewing angle. The support arm further can comprise a system level powerbutton and USB and ethernet connectors.

The robotic arm can be mounted to the mobile therapy cart on arm base ofsufficient height to allow reach and ease of use positioning the arm invarious drive modes into the patient/procedure work space from set up,through the procedure, and take down. The robotic arm can comprise sixdegrees of freedom with six rotating joints, a reach of 850 mm and amaximum payload of 5 kg. The arm may be controlled through thehistotripsy system software as well as a 12 inch touchscreen polyscopewith a graphical user interface. The robot can comprise force sensingand a tool flange, with force (x, y, z) with a range of 50 N, precisionof 3.5 N and accuracy of 4.0 N, and torque (x, y, z) with a range of10.0 Nm, precision of 0.2 Nm and accuracy of 0.3 Nm. The robot has apose repeatability of +/−0.03 mm and a typical TCP speed of 1 m/s (39.4in/s). In one embodiment, the robot control box has multiple I/O ports,including 16 digital in, 16 digital out, 2 analog in, 2 analog out and 4quadrature digital inputs, and an I/O power supply of 24V/2 A. Thecontrol box communication comprises 500 Hz control frequency, ModbusTCP, PROFINET, ethernet/IP and USB 2.0 and 3.0.

The therapy head can comprise one of a select group of four histotripsytherapy transducers and an ultrasound imaging system/probe, coaxiallylocated in the therapy transducer, with an encoded mechanism to rotatesaid imaging probe independent of the therapy transducer to knownpositions, and a handle to allow gross and fine positioning of thetherapy head, including user inputs for activating the robot (e.g. forfree drive positioning). In some examples, the therapy transducers mayvary in size (22×17 cm to 28×17 cm), focal lengths from 12-18 cm, numberof elements, ranging from 48 to 64 elements, comprised within 12-16rings, and all with a frequency of 700 kHz. The therapy head subsystemhas an interface to the robotic arm includes a quick release mechanismto allow removing and/or changing the therapy head to allow cleaning,replacement and/or selection of an alternative therapy transducer design(e.g. of different number of elements and geometry), and each therapytransducer is electronically keyed for auto-identification in the systemsoftware.

The patient coupling system can comprise a six degree of freedom, sixjoint, mechanical arm, configured with a mounting bracket designed tointerface to a surgical/interventional table rail. The arm may have amaximum reach of approximately 850 mm and an average diameter of 50 mm.The distal end of the arm can be configured to interface with anultrasound medium container, including a frame system and an upper andlower boot. The lower boot is configured to support either a patientcontacting film, sealed to patient, or an elastic polymer membrane, bothdesigned to contain ultrasound medium (e.g. degassed water or watermixture), either within the frame and boot and in direct contact withthe patient, or within the membrane/boot construct. The lower bootprovides, in one example, a top and bottom window of approximately 46cm×56 cm and 26 cm×20 cm, respectively, for placing the therapytransducer with the ultrasound medium container and localized on thepatient's abdomen. The upper boot may be configured to allow the distalend of the robot to interface to the therapy head and/or transducer, andto prevent water leakage/spillage. In preferred embodiments, the upperboot is a sealed system. The frame is also configured, in a sealedsystem, to allow two-way fluid communication between the ultrasoundmedium container and an ultrasound medium source (e.g. reservoir orfluidics management system), including, but not limited for filling anddraining, as well as air venting for bubble management.

The system software and work-flow can be configured to allow users tocontrol the system through touchscreen display and the physicalcontrols, including but not limited to, ultrasound imaging parametersand therapy parameters. The graphical user interface of the systemcomprises a work-flow based flow, with the general procedure steps of 1)registering/selecting a patient, 2) planning, comprising imaging thepatient (and target location/anatomy) with the freehand imaging probe,and robot assisted imaging with the transducer head for final gross andfine targeting, including contouring the target with a target and margincontour, of which are typically spherical and ellipsoidal in nature, andrunning a test protocol (e.g. test pulses) including a bubble cloudcalibration step, and a series of predetermined locations in the volumeto assess cavitation initiation threshold and other patient/targetspecific parameters (e.g. treatment depth), that together inform atreatment plan accounting for said target's location and acousticpathway, and any related blockage (e.g. tissue interfaces, bone, etc.)that may require varied levels of drive amplitude to initiate andmaintain histotripsy. Said parameters, as measured as a part of the testprotocol, comprising calibration and multi-location test pulses, areconfigured in the system to provide input/feedback for updating bubblecloud location in space as needed/desired (e.g. appropriately calibratedto target cross-hairs), as well as determining/interpolating requiredamplitudes across all bubble cloud treatment locations in the treatmentvolume to ensure threshold is achieved throughout the volume. Further,said parameters, including but not limited to depth and drive voltage,may be also used as part of an embedded treatability matrix or look uptable to determine if additional cooling is required (e.g. off-time inaddition to time allocated to robot motions between treatment patternmovements) to ensure robust cavitation and intervening/collateralthermal effects are managed (e.g. staying below t43 curve for any knownor calculated combination of sequence, pattern and pathway, and targetdepth/blockage). The work-flow and procedure steps associated with thesefacets of planning, as implemented in the system software may beautomated, wherein the robot and controls system are configured to runthrough the test protocol and locations autonomously, orsemi-autonomously. Following planning, the next phase of the procedurework-flow, 3) the treatment phase, is initiated following the useraccepting the treatment plan and initiating the system for treatment.Following this command, the system is configured to deliver treatmentautonomously, running the treatment protocol, until the prescribedvolumetric treatment is complete. The status of the treatment (andlocation of the bubble cloud) is displayed in real-time, adjacent tovarious treatment parameters, including, but not limited to, of whichmay include total treatment time and remaining treatment time, drivevoltage, treatment contours (target/margin) and bubble cloud/pointlocations, current location in treatment pattern (e.g. slice andcolumn), imaging parameters, and other additional contextual data (e.g.optional DICOM data, force torque data from robot, etc.). Followingtreatment, the user may use the therapy head probe, and subsequently,the freehand ultrasound probe to review and verify treatment, ascontrolled/viewed through the system user interface. If additionaltarget locations are desired, the user may plan/treat additionaltargets, or dock the robot to a home position on the cart if no furthertreatments are planned.

FIG. 1A generally illustrates histotripsy system 100 according to thepresent disclosure, comprising a therapy transducer 102, an imagingsystem 104, a display and control panel 106, a robotic positioning arm108, and a cart 110. The system can further include an ultrasoundcoupling interface and a source of coupling medium, not shown.

FIG. 1B is a bottom view of the therapy transducer 102 and the imagingsystem 104. As shown, the imaging system can be positioned in the centerof the therapy transducer. However, other embodiments can include theimaging system positioned in other locations within the therapytransducer, or even directly integrated into the therapy transducer. Insome embodiments, the imaging system is configured to produce real-timeimaging at a focal point of the therapy transducer.

The histotripsy system may comprise one or more of various sub-systems,including a Therapy sub-system that can create, apply, focus and deliveracoustic cavitation/histotripsy through one or more therapy transducers,Integrated Imaging sub-system (or connectivity to) allowing real-timevisualization of the treatment site and histotripsy effect through-outthe procedure, a Robotics positioning sub-system to mechanically and/orelectronically steer the therapy transducer, further enabled toconnect/support or interact with a Coupling sub-system to allow acousticcoupling between the therapy transducer and the patient, and Software tocommunicate, control and interface with the system and computer-basedcontrol systems (and other external systems) and various OtherComponents, Ancillaries and Accessories, including one or more userinterfaces and displays, and related guided work-flows, all working inpart or together. The system may further comprise various fluidics andfluid management components, including but not limited to, pumps, valveand flow controls, temperature and degassing controls, and irrigationand aspiration capabilities, as well as providing and storing fluids. Itmay also contain various power supplies and protectors.

Cart

The Cart 110 may be generally configured in a variety of ways and formfactors based on the specific uses and procedures. In some cases,systems may comprise multiple Carts, configured with similar ordifferent arrangements. In some embodiments, the cart may be configuredand arranged to be used in a radiology environment and in some cases inconcert with imaging (e.g., CT, cone beam CT and/or MRI scanning). Inother embodiments, it may be arranged for use in an operating room and asterile environment, or in a robotically enabled operating room, andused alone, or as part of a surgical robotics procedure wherein asurgical robot conducts specific tasks before, during or after use ofthe system and delivery of acoustic cavitation/histotripsy. As such anddepending on the procedure environment based on the aforementionedembodiments, the cart may be positioned to provide sufficient work-spaceand access to various anatomical locations on the patient (e.g., torso,abdomen, flank, head and neck, etc.), as well as providing work-spacefor other systems (e.g., anesthesia cart, laparoscopic tower, surgicalrobot, endoscope tower, etc.).

The Cart may also work with a patient surface (e.g., table or bed) toallow the patient to be presented and repositioned in a plethora ofpositions, angles and orientations, including allowing changes to suchto be made pre, peri and post-procedurally. It may further comprise theability to interface and communicate with one or more external imagingor image data management and communication systems, not limited toultrasound, CT, fluoroscopy, cone beam CT, PET, PET/CT, MRI, optical,ultrasound, and image fusion and or image flow, of one or moremodalities, to support the procedures and/or environments of use,including physical/mechanical interoperability (e.g. compatible withincone beam CT work-space for collecting imaging data pre, peri and/orpost histotripsy).

In some embodiments one or more Carts may be configured to worktogether. As an example, one Cart may comprise a bedside mobile Cartequipped with one or more Robotic arms enabled with a Therapytransducer, and Therapy generator/amplifier, etc., while a companioncart working in concert and at a distance of the patient may compriseIntegrated Imaging and a console/display for controlling the Robotic andTherapy facets, analogous to a surgical robot and master/slaveconfigurations.

In some embodiments, the system may comprise a plurality of Carts, allslave to one master Cart, equipped to conduct acoustic cavitationprocedures. In some arrangements and cases, one Cart configuration mayallow for storage of specific sub-systems at a distance reducingoperating room clutter, while another in concert Cart may compriseessentially bedside sub-systems and componentry (e.g., delivery systemand therapy).

One can envision a plethora of permutations and configurations of Cartdesign, and these examples are in no way limiting the scope of thedisclosure.

Histotripsy

Histotripsy comprises short, high amplitude, focused ultrasound pulsesto generate a dense, energetic, “bubble cloud”, capable of the targetedfractionation and destruction of tissue. Histotripsy is capable ofcreating controlled tissue erosion when directed at a tissue interface,including tissue/fluid interfaces, as well as well-demarcated tissuefractionation and destruction, at sub-cellular levels, when it istargeted at bulk tissue. Unlike other forms of ablation, includingthermal and radiation-based modalities, histotripsy does not rely onheat or ionizing (high) energy to treat tissue. Instead, histotripsyuses acoustic cavitation generated at the focus to mechanically effecttissue structure, and in some cases liquefy, suspend, solubilize and/ordestruct tissue into sub-cellular components.

Histotripsy can be applied in various forms, including: 1)Intrinsic-Threshold Histotripsy: Delivers pulses with at least a singlenegative/tensile phase sufficient to cause a cluster of bubble nucleiintrinsic to the medium to undergo inertial cavitation, 2)Shock-Scattering Histotripsy: Delivers typically pulses 3-20 cycles induration. The amplitude of the tensile phases of the pulses issufficient to cause bubble nuclei in the medium to undergo inertialcavitation within the focal zone throughout the duration of the pulse.These nuclei scatter the incident shockwaves, which invert andconstructively interfere with the incident wave to exceed the thresholdfor intrinsic nucleation, and 3) Boiling Histotripsy: Employs pulsesroughly 1-20 ms in duration. Absorption of the shocked pulse rapidlyheats the medium, thereby reducing the threshold for intrinsic nuclei.Once this intrinsic threshold coincides with the peak negative pressureof the incident wave, boiling bubbles form at the focus.

The large pressure generated at the focus causes a cloud of acousticcavitation bubbles to form above certain thresholds, which createslocalized stress and strain in the tissue and mechanical breakdownwithout significant heat deposition. At pressure levels where cavitationis not generated, minimal effect is observed on the tissue at the focus.This cavitation effect is observed only at pressure levels significantlygreater than those which define the inertial cavitation threshold inwater for similar pulse durations, on the order of 10 to 30 MPa peaknegative pressure.

Histotripsy may be performed in multiple ways and under differentparameters. It may be performed totally non-invasively by acousticallycoupling a focused ultrasound transducer over the skin of a patient andtransmitting acoustic pulses transcutaneously through overlying (andintervening) tissue to the focal zone (treatment zone and site). It maybe further targeted, planned, directed and observed under directvisualization, via ultrasound imaging, given the bubble clouds generatedby histotripsy may be visible as highly dynamic, echogenic regions on,for example, B Mode ultrasound images, allowing continuous visualizationthrough its use (and related procedures). Likewise, the treated andfractionated tissue shows a dynamic change in echogenicity (typically areduction), which can be used to evaluate, plan, observe and monitortreatment.

Generally, in histotripsy treatments, ultrasound pulses with 1 or moreacoustic cycles are applied, and the bubble cloud formation relies onthe pressure release scattering of the positive shock fronts (sometimesexceeding 100 MPa, P+) from initially initiated, sparsely distributedbubbles (or a single bubble). This is referred to as the “shockscattering mechanism”.

This mechanism depends on one (or a few sparsely distributed) bubble(s)initiated with the initial negative half cycle(s) of the pulse at thefocus of the transducer. A cloud of microbubbles then forms due to thepressure release backscattering of the high peak positive shock frontsfrom these sparsely initiated bubbles. These back-scatteredhigh-amplitude rarefactional waves exceed the intrinsic threshold thusproducing a localized dense bubble cloud. Each of the following acousticcycles then induces further cavitation by the backscattering from thebubble cloud surface, which grows towards the transducer. As a result,an elongated dense bubble cloud growing along the acoustic axis oppositethe ultrasound propagation direction is observed with the shockscattering mechanism. This shock scattering process makes the bubblecloud generation not only dependent on the peak negative pressure, butalso the number of acoustic cycles and the amplitudes of the positiveshocks. Without at least one intense shock front developed by nonlinearpropagation, no dense bubble clouds are generated when the peak negativehalf-cycles are below the intrinsic threshold.

When ultrasound pulses less than 2 cycles are applied, shock scatteringcan be minimized, and the generation of a dense bubble cloud depends onthe negative half cycle(s) of the applied ultrasound pulses exceeding an“intrinsic threshold” of the medium. This is referred to as the“intrinsic threshold mechanism”.

This threshold can be in the range of 26-30 MPa for soft tissues withhigh water content, such as tissues in the human body. In someembodiments, using this intrinsic threshold mechanism, the spatialextent of the lesion may be well-defined and more predictable. With peaknegative pressures (P−) not significantly higher than this threshold,sub-wavelength reproducible lesions as small as half of the −6 dB beamwidth of a transducer may be generated.

With high-frequency Histotripsy pulses, the size of the smallestreproducible lesion becomes smaller, which is beneficial in applicationsthat require precise lesion generation. However, high-frequency pulsesare more susceptible to attenuation and aberration, renderingproblematical treatments at a larger penetration depth (e.g., ablationdeep in the body) or through a highly aberrative medium (e.g.,transcranial procedures, or procedures in which the pulses aretransmitted through bone(s)). Histotripsy may further also be applied asa low-frequency “pump” pulse (typically <2 cycles and having a frequencybetween 100 kHz and 1 MHz) can be applied together with a high-frequency“probe” pulse (typically <2 cycles and having a frequency greater than 2MHz, or ranging between 2 MHz and 10 MHz) wherein the peak negativepressures of the low and high-frequency pulses constructively interfereto exceed the intrinsic threshold in the target tissue or medium. Thelow-frequency pulse, which is more resistant to attenuation andaberration, can raise the peak negative pressure P− level for a regionof interest (ROI), while the high-frequency pulse, which provides moreprecision, can pin-point a targeted location within the ROI and raisethe peak negative pressure P− above the intrinsic threshold. Thisapproach may be referred to as “dual frequency”, “dual beam histotripsy”or “parametric histotripsy.”

Additional systems, methods and parameters to deliver optimizedhistotripsy, using shock scattering, intrinsic threshold, and variousparameters enabling frequency compounding and bubble manipulation, areherein included as part of the system and methods disclosed herein,including additional means of controlling said histotripsy effect aspertains to steering and positioning the focus, and concurrentlymanaging tissue effects (e.g., prefocal thermal collateral damage) atthe treatment site or within intervening tissue. Further, it isdisclosed that the various systems and methods, which may include aplurality of parameters, such as but not limited to, frequency,operating frequency, center frequency, pulse repetition frequency,pulses, bursts, number of pulses, cycles, length of pulses, amplitude ofpulses, pulse period, delays, burst repetition frequency, sets of theformer, loops of multiple sets, loops of multiple and/or different sets,sets of loops, and various combinations or permutations of, etc., areincluded as a part of this disclosure, including future envisionedembodiments of such.

Therapy Components

The Therapy sub-system may work with other sub-systems to create,optimize, deliver, visualize, monitor and control acoustic cavitation,also referred to herein and in following as “histotripsy”, and itsderivatives of, including boiling histotripsy and other thermal highfrequency ultrasound approaches. It is noted that the disclosedinventions may also further benefit other acoustic therapies that do notcomprise a cavitation, mechanical or histotripsy component. The therapysub-system can include, among other features, an ultrasound therapytransducer and a pulse generator system configured to deliver ultrasoundpulses into tissue.

In order to create and deliver histotripsy and derivatives ofhistotripsy, the therapy sub-system may also comprise components,including but not limited to, one or more function generators,amplifiers, therapy transducers and power supplies.

The therapy transducer can comprise a single element or multipleelements configured to be excited with high amplitude electric pulses(>1000V or any other voltage that can cause harm to living organisms).The amplitude necessary to drive the therapy transducers for Histotripsyvary depending on the design of the transducer and the materials used(e.g., solid or polymer/piezoelectric composite including ceramic orsingle crystal) and the transducer center frequency which is directlyproportional to the thickness of the piezo-electric material.Transducers therefore operating at a high frequency require lowervoltage to produce a given surface pressure than is required by lowfrequency therapy transducers. In some embodiments, the transducerelements are formed using a piezoelectric-polymer composite material ora solid piezoelectric material. Further, the piezoelectric material canbe of polycrystalline/ceramic or single crystalline formulation. In someembodiments the transducer elements can be formed using silicon usingMEMs technology, including CMUT and PMUT designs.

In some embodiments, the function generator may comprise a fieldprogrammable gate array (FPGA) or other suitable function generator. TheFPGA may be configured with parameters disclosed previously herein,including but not limited to frequency, pulse repetition frequency,bursts, burst numbers, where bursts may comprise pulses, numbers ofpulses, length of pulses, pulse period, delays, burst repetitionfrequency or period, where sets of bursts may comprise a parameter set,where loop sets may comprise various parameter sets, with or withoutdelays, or varied delays, where multiple loop sets may be repeatedand/or new loop sets introduced, of varied time delay and independentlycontrolled, and of various combinations and permutations of such,overall and throughout.

In some embodiments, the generator or amplifier may be configured to bea universal single-cycle or multi-cycle pulse generator, and to supportdriving via Class D or inductive driving, as well as across allenvisioned clinical applications, use environments, also discussed inpart later in this disclosure. In other embodiments, the class D orinductive current driver may be configured to comprise transformerand/or auto-transformer driving circuits to further provide step up/downcomponents, and in some cases, to preferably allow a step up in theamplitude. They may also comprise specific protective features, tofurther support the system, and provide capability to protect otherparts of the system (e.g., therapy transducer and/or amplifier circuitcomponents) and/or the user, from various hazards, including but notlimited to, electrical safety hazards, which may potentially lead to useenvironment, system and therapy system, and user harms, damage orissues.

Disclosed generators may allow and support the ability of the system toselect, vary and control various parameters (through enabled softwaretools), including, but not limited to those previously disclosed, aswell as the ability to start/stop therapy, set and read voltage level,pulse and/or burst repetition frequency, number of cycles, duty ratio,channel enabled and delay, etc., modulate pulse amplitude on a fasttime-scale independent of a high voltage supply, and/or other service,diagnostic or treatment features.

In some embodiments, the Therapy sub-system and/or components of, suchas the amplifier, may comprise further integrated computer processingcapability and may be networked, connected, accessed, and/or beremovable/portable, modular, and/or exchangeable between systems, and/ordriven/commanded from/by other systems, or in various combinations.Other systems may include other acoustic cavitation/histotripsy, HIFU,HITU, radiation therapy, radiofrequency, microwave, and cryoablationsystems, navigation and localization systems, laparoscopic, singleincision/single port, endoscopic and non-invasive surgical robots,laparoscopic or surgical towers comprising other energy-based or visionsystems, surgical system racks or booms, imaging carts, etc.

In some embodiments, one or more amplifiers may comprise a Class Damplifier and related drive circuitry including matching networkcomponents. Depending on the transducer element electric impedance andchoice of the matching network components (e.g., an LC circuit made ofan inductor L1 in series and the capacitor C1 in parallel), the combinedimpedance can be aggressively set low in order to have high amplitudeelectric waveform necessary to drive the transducer element. The maximumamplitude that Class D amplifiers is dependent on the circuit componentsused, including the driving MOSFET/IGBT transistors, matching networkcomponents or inductor, and transformer or autotransformer, and of whichmay be typically in the low kV (e.g., 1-3 kV) range.

Therapy transducer element(s) are excited with an electrical waveformwith an amplitude (voltage) to produce a pressure output sufficient forHistotripsy therapy. The excitation electric field can be defined as thenecessary waveform voltage per thickness of the piezoelectric element.For example, because a piezoelectric element operating at 1 MHztransducer is half the thickness of an equivalent 500 kHz element, itwill require half the voltage to achieve the same electric field andsurface pressure.

To sufficiently drive therapy transducers for histotripsy therapy, inother embodiments, the amplifier maybe required to produce voltages thatexceed operational limits of conventional amplifier circuit components.For example, FIG. 2 provides a schematic diagram of an inductive drivercircuit configured to excite ultrasound transducers for histotripsytherapy. With the inductive driver circuit of FIG. 2 , therapytransducer elements can be driven up to approximately 3 kV peak-positiveor up to about 4.5 kV peak-to-peak. These voltages may, for example, beadequate for a therapy transducer operating at 1 MHz but not sufficientfor a 500 kHz transducer. The maximum driving voltage in this example ofthe inductive driver is limited by the maximum operating voltage of theIGBT transistor Q1 and its switching time. The IGBT transistor with bestperformance for the inductive driving circuit currently available israted for maximum of 3 kV. It should be understood that this drivingvoltage can improve as advances in transistors are made.

The inductive driver circuit described above also offers many advantagesto higher frequency transducers, including the ability to producesmaller/more precise bubble clouds (i.e., microtripsy), producing areduced thermal effect in tissue, etc.

The inductive driver circuit of FIG. 2 is designed and configured to usethe transducer element as a capacitor in parallel to the L1 inductor inorder to create an oscillating circuit. When the IGBT transistor isexcited with a single pulse, current flows through the inductor L1 whichtemporarily stores the energy in a magnetic field. As soon as drivingpulse disappears, magnetic field is transferred back to very highamplitude electric pulse and process keeps repeating on the resonantfrequency of the LC circuit (L1 and Y1 in the illustrated example). Timethat is needed for inductor to be charged (aka. charging time) can varyand will proportionally affect the output amplitude. This high electricpulse is limited to 3 kV peak-positive as described above.

Although the inductive driver circuit of FIG. 2 provides higher voltagesover typical Class D amplifiers, it has its own limitations, includingthat 1) it can be driven with only one pulse at a time. Multiple cyclesare possible with increased spacing between pulses that allows forinductor charging for the next cycle; 2) in case of accidentaldisconnection of the transducer element, the resonant circuit will startoscillating in much higher frequency and produce amplitudes that mayexceed 3 kV peak-positive which could destroy the IGBT transistor andcreate catastrophic failure of the system; 3) if a transducer elementbecomes shorted, the current will bypass the inductor and will beshorted directly to the ground through the IGBT transistor Q1, whichcould cause a drop in the high voltage supply or failure of the IGBTtransistor due to the excessive current; and 4) the inductive drivercircuit is currently limited to approximately 3 kV peak-positive orabout 4.5 kV peak-to-peak.

FIG. 3 illustrates a schematic diagram of an autotransforming inductivedriver circuit including an inductor Lx with a center tap that solvesthe shortcomings of the inductive driver circuit of FIG. 2 . In thisembodiment, the driving signal is generated in the generator G1 andpasses through the resistor R1 to the optically isolated IGBT driver U1.As a result, a driving square wave pulse with amplitude of 15V isgenerated at U1 pins 6 and 7 and applied to the gate of the IGBTtransistor Q1. When signal at the gate is high (e.g., 15V), thetransistor Q1 opens and current from “+HV” terminal flows through thefirst portion of the Lx inductor (L1), through diode D1, and through thetransistor Q1 (collector to emitter) to the GND. Capacitor C3 is abypass capacitor that supports momentarily current draw by the circuit.C3 has voltage rating that exceeds maximum “+HV” voltage and as muchcapacitance as necessary to support momentarily current draw. Electricalcurrent that flows through the one part of the inductor Lx (L1) createsa magnetic field and charges the inductor Lx. As soon as driving signalgoes to low, the IGBT transistor Q1 closes, and magnetic field (energy)that is created in the first part L1 of the inductor Lx is stored in theentire inductor Lx and is transformed to the electric energy across theentire inductor Lx (Lx=L1+L2).

Varying the supply voltage “+HV” in the range 0-1000V DC and varying thecharging time or width of the driving pulse in the range 0-10 us, peakvoltage at the center tap of the inductor Lx (where L1 is connected toL2) can reach up to 3000V peak-positive which is limited by thetransistor Q1 as described earlier in the inductive driving circuit ofFIG. 2 . Since the inductor Lx of FIG. 3 is not just a regular inductor,but an inductor with a center tap, that makes it an autotransformer.Depending of the turn ratio between one part of the inductor Lx (L1) andthe other part L2, voltage across the inductor Lx can be customized. Forexample: If center tap of the inductor Lx is at the center of theinductor, then the ratio between L1 to Lx will be 1 to 2 (1:2). Thismeans that if maximum voltage generated at the L1, can be effectivelydoubled using autotransformer inductor as described here, and in thiscase, generate up to 6000V peak-positive across Lx which is applied tothe therapy transducer Y1. For the therapy transducers with loweroperating frequencies, higher voltage may be required in order to obtaindesirable acoustic output. In that case different design of Lx withcustomized ratio L1:Lx is required. Using this approach (more aggressiveturn ratio L1:Lx), voltages generated across Lx could be extremely highand it will be limited only by isolation limitations to safely handlethe produced high voltage pulses.

As described above, the autotransformer Lx of FIG. 3 in combination withcapacitor C1 and the therapy transducer Y1 creates a resonant circuitconfigured to be used as a pulse generator able to generate very highvoltage AC pulses for driving a therapy transducer, which producesmaximum acoustic output needed for Histotripsy therapy.

The total value of the inductor Lx of FIG. 3 can be determined based onthe electric impedance and operating frequency of the transducerelement. In some examples, the value of the inductor Lx can bedetermined based on the optimally desired acoustical output (desiredfrequency of the pulses, peak positive and peak negative pressures pervoltage in, etc. . . . ). For Histotripsy, the application total valueof the inductor Lx could be in range of 1-1000 uH.

As described above, the center frequency of the therapy transducer isproportional to the thickness of the piezoelectric material that thetherapy transducer is made of. Therefore, the thickness of thepiezoelectric will determine maximum safe operating voltage needed inorder to output maximum acoustic pressure. Additionally, the maximumoperating voltage will determine the inductor (autotransformer) turnratio (L1:Lx) needed. In other words, it will determine where on theinductor winding a center tap needs to be placed which when placed turnsthe inductor into the autotransformer.

Capacitor C1 in the circuit of FIG. 3 is a very important part of thecircuit. Connected together in parallel with part of the autotransformerL1, the capacitor C1 creates a resonant circuit that oscillates in samefrequency as the autotransformer Lx in parallel with the therapytransducer Y1. The voltage rating of the capacitor C1 should be at least10% higher than the maximum driving voltage. The capacitance value ofthe capacitor C1 is determined using the following formula forcalculating resonant frequency:

$f_{0} = {\frac{\omega}{2\pi} = \frac{1}{2\pi\sqrt{LC}}}$

However, a slight change of the capacitor value can fine tune theresonant frequency of the entire circuit. It is recommended that finalvalue of the capacitor be determined by desired acoustical output(peak-positive pressure, peak-negative pressure, frequency, etc. . . .). For Histotripsy therapy, for example, the value of the capacitor C1could be in range of 100 pF-100 nF.

The capacitor C1 of FIG. 3 can be substituted with another active orpassive electronic component such as a resistor, diode, inductor, etc.as well as a combination of multiple different components. For example:if a capacitor C1 is substituted with the combination of components likecapacitor Cx, diode Dx, and resistor Rx in a manner shown in FIG. 4 , itis possible to obtain even more asymmetric waveform with larger negativepeak or larger positive peak depending on the orientation of the diodeDx. The level of asymmetry is determined by the value of the resistor Rxand the frequency by the value of the capacitor Cx. The switchingtransistor Q4 can be an IGBT transistor, or any other high-powerswitching devices like MOSFET, Bipolar Transistors, or others.

The autotransforming inductive driver circuit of FIG. 3 provides theability to create very high amplitudes without the limitations of classD and the inductive driver generators described above. As mentioned, incase of a single fault condition where the therapy transducer getsdisconnected, very high voltage peaks that can destroy the IGBTtransistor Q1 will not be generated by the autotransforming inductivedriver circuit and therefore the catastrophic failure of the system willnot occur. In event of this situation, the IGBT transistor Q1 continuesto operate in normal conditions because of the resonant circuitcomprised of the capacitor C1 and the inductor L1 (primary portion ofthe autotransformer Lx) are still operating normally as they were if thetherapy transducer Y1 is connected.

In case of a single fault condition where the therapy transducer getsshorted, extensive current flow that can destroy the IGBT transistor Q1,or shorting of the high voltage power Supply “+HV” will not occur andtherefore the catastrophic failure of the system will not occur as itwould with a regular inductive driver generator. The IGBT transistor Q1continues to operate in normal conditions because of the resonantcircuit comprised of the capacitor C1 and the inductor L1 (primaryportion of the autotransformer Lx) are still operating normally as theywere if the therapy transducer Y1 is connected.

Alternatively, for additional safety for the service personnel and usersin general, the auto transforming inductive driver circuit of FIG. 3 canbe supplied with the negative voltage supply. In that case +HV terminalsas shown in the figures described above can be connected to the ground(GND) and ground terminals can be connected to the negative voltagesupply (−HV) as shown in the FIG. 5 . Note that the 15V power supply isin reference to the −HV terminal. This is easily obtained using isolatedDC/DC converter where the negative secondary terminal is connected tothe −HV terminal. That isolated DC/DC converter has to be properly ratedfor the level of −HV power supply.

The main safety benefit of the negative voltage supply is that one ofthe electrodes (typically shielding of the BNC or another connector) ofthe transducer is always connected to the ground (GND) and thereforesafe for the operator or service person to touch, connect or disconnectthe transducer while the amplifier is energized. If the circuit issupplied conventionally with positive supply voltage, one electrode ofthe transducer will be connected to the high voltage power supply andtherefore not safe to be handled.

It is also possible to apply the protective circuit of FIG. 5 by addingthe capacitor C1 in parallel to the inductor L1 and the ultrasonictransducer Y1 shown in FIG. 6 . The value of the capacitor C1 can becalculated to be as minimal as needed to have the oscillating circuitoscillate within safe frequency and voltage angle ranges to preventgeneration of voltages that exceed the working voltage of the transistorQ1 in the event that the ultrasonic transducer gets disconnected orfails with an open circuit.

The combined capacitance of the capacitor C1 and the transducer Y1 isused to calculate the working frequency of the resonant circuit (i.e.,capacitor C1, inductor L1, and ultrasonic transducer Y1). Alternatively,changing the value of the capacitor C1 can be used to fine-tune theoperating frequency of the entire circuit.

In the event of the short circuit failure mode of the transducer, thefast-acting fuse is connected in series to the power source +HV. Thevalue of the fast-acting fuse F1 is calculated to be a 10% or higherthan the current consumption of the entire circuit at the maximumamplitude and duty cycle. If a failure occurs, direct current will startflowing through the shorted transducer Y1 and the transistor Q1. At thattime, the fast-acting fuse F1 will open due to the excessive currentwhich will protect the transistor Q1 and the entire system fromcatastrophic failure.

The Therapy sub-system may also comprise therapy transducers of variousdesigns and working parameters, supporting use in various procedures(and procedure settings). Systems may be configured with one or moretherapy transducers, that may be further interchangeable, and work withvarious aspects of the system in similar or different ways (e.g., mayinterface to a robotic arm using a common interface and exchangefeature, or conversely, may adapt to work differently with applicationspecific imaging probes, where different imaging probes may interfaceand integrate with a therapy transducer in specifically different ways).

Therapy transducers may be configured of various parameters that mayinclude size, shape (e.g., rectangular or round; anatomically curvedhousings, etc.), geometry, focal length, number of elements, size ofelements, distribution of elements (e.g., number of rings, size of ringsfor annular patterned transducers), frequency, enabling electronic beamsteering, etc. Transducers may be composed of various materials (e.g.,piezoelectric, silicon, etc.), form factors and types (e.g., machinedelements, chip-based, etc.) and/or by various methods of fabrication of.

Transducers may be designed and optimized for clinical applications(e.g., abdominal tumors, peripheral vascular disease, fat ablation,etc.) and desired outcomes (e.g., acoustic cavitation/histotripsywithout thermal injury to intervening tissue), and affording a breadthof working ranges, including relatively shallow and superficial targets(e.g., thyroid or breast nodules), versus, deeper or harder to reachtargets, such as central liver or brain tumors. They may be configuredto enable acoustic cavitation/histotripsy under various parameters andsets of, as enabled by the aforementioned system components (e.g.,function generator and amplifier, etc.), including but not limited tofrequency, pulse repetition rate, pulses, number of pulses, pulselength, pulse period, delays, repetitions, sync delays, sync period,sync pulses, sync pulse delays, various loop sets, others, andpermutations of.

Integrated Imaging

The disclosed system may comprise various imaging modalities to allowusers to visualize, monitor and collect/use feedback of the patient'sanatomy, related regions of interest and treatment/procedure sites, aswell as surrounding and intervening tissues to assess, plan and conductprocedures, and adjust treatment parameters as needed. Imagingmodalities may comprise various ultrasound, x-ray, CT, MRI, PET,fluoroscopy, optical, contrast or agent enhanced versions, and/orvarious combinations of. It is further disclosed that various imageprocessing and characterization technologies may also be utilized toafford enhanced visualization and user decision making. These may beselected or commanded manually by the user or in an automated fashion bythe system. The system may be configured to allow side by side,toggling, overlays, 3D reconstruction, segmentation, registration,multi-modal image fusion, image flow, and/or any methodology affordingthe user to identify, define and inform various aspects of using imagingduring the procedure, as displayed in the various system user interfacesand displays. Examples may include locating, displaying andcharacterizing regions of interest, organ systems, potential treatmentsites within, with on and/or surrounding organs or tissues, identifyingcritical structures such as ducts, vessels, nerves, ureters, fissures,capsules, tumors, tissue trauma/injury/disease, other organs, connectivetissues, etc., and/or in context to one another, of one or more (e.g.,tumor draining lymphatics or vasculature; or tumor proximity to organcapsule or underlying other organ), as unlimited examples.

Systems may be configured to include onboard integrated imaginghardware, software, sensors, probes and wetware, and/or may beconfigured to communicate and interface with external imaging and imageprocessing systems. The aforementioned components may be also integratedinto the system's Therapy sub-system components wherein probes, imagingarrays, or the like, and electrically, mechanically orelectromechanically integrated into therapy transducers. This mayafford, in part, the ability to have geometrically aligned imaging andtherapy, with the therapy directly within the field of view, and in somecases in line, with imaging. In some embodiments, this integration maycomprise a fixed orientation of the imaging capability (e.g., imagingprobe) in context to the therapy transducer. In other embodiments, theimaging solution may be able to move or adjust its position, includingmodifying angle, extension (e.g., distance from therapy transducer orpatient), rotation (e.g., imaging plane in example of an ultrasoundprobe) and/or other parameters, including moving/adjusting dynamicallywhile actively imaging. The imaging component or probe may be encoded soits orientation and position relative to another aspect of the system,such as the therapy transducer, and/or robotically-enabled positioningcomponent may be determined.

In one embodiment, the system may comprise onboard ultrasound, furtherconfigured to allow users to visualize, monitor and receive feedback forprocedure sites through the system displays and software, includingallowing ultrasound imaging and characterization (and various forms of),ultrasound guided planning and ultrasound guided treatment, all inreal-time. The system may be configured to allow users to manually,semi-automated or in fully automated means image the patient (e.g., byhand or using a robotically-enabled imager).

In some embodiments, imaging feedback and monitoring can includemonitoring changes in: backscatter from bubble clouds; speckle reductionin backscatter; backscatter speckle statistics; mechanical properties oftissue (i.e., elastography); tissue perfusion (i.e. ultrasoundcontrast); shear wave propagation; acoustic emissions, electricalimpedance tomography, and/or various combinations of, including asdisplayed or integrated with other forms of imaging (e.g., CT or MRI).

In some embodiments, imaging including feedback and monitoring frombackscatter from bubble clouds, may be used as a method to determineimmediately if the histotripsy process has been initiated, is beingproperly maintained, or even if it has been extinguished. For example,this method enables continuously monitored in real time drug delivery,tissue erosion, and the like. The method also can provide feedbackpermitting the histotripsy process to be initiated at a higher intensityand maintained at a much lower intensity. For example, backscatterfeedback can be monitored by any transducer or ultrasonic imager. Bymeasuring feedback for the therapy transducer, an accessory transducercan send out interrogation pulses or be configured to passively detectcavitation. Moreover, the nature of the feedback received can be used toadjust acoustic parameters (and associated system parameters) tooptimize the drug delivery and/or tissue erosion process.

In some embodiments, imaging including feedback and monitoring frombackscatter, and speckle reduction, may be configured in the system.

For systems comprising feedback and monitoring via backscattering, andas means of background, as tissue is progressively mechanicallysubdivided, in other words homogenized, disrupted, or eroded tissue,this process results in changes in the size and distribution of acousticscatter. At some point in the process, the scattering particle size anddensity is reduced to levels where little ultrasound is scattered, orthe amount scattered is reduced significantly. This results in asignificant reduction in speckle, which is the coherent constructive anddestructive interference patterns of light and dark spots seen on imageswhen coherent sources of illumination are used; in this case,ultrasound. After some treatment time, the speckle reduction results ina dark area in the therapy volume. Since the amount of speckle reductionis related to the amount of tissue subdivision, it can be related to thesize of the remaining tissue fragments. When this size is reduced tosub-cellular levels, no cells are assumed to have survived. So,treatment can proceed until a desired speckle reduction level has beenreached. Speckle is easily seen and evaluated on standard ultrasoundimaging systems. Specialized transducers and systems, including thosedisclosed herein, may also be used to evaluate the backscatter changes.

Further, systems comprising feedback and monitoring via speckle, and asmeans of background, an image may persist from frame to frame and changevery little as long as the scatter distribution does not change andthere is no movement of the imaged object. However, long before thescatters are reduced enough in size to cause speckle reduction, they maybe changed sufficiently to be detected by signal processing and othermeans. This family of techniques can operate as detectors of specklestatistics changes. For example, the size and position of one or morespeckles in an image will begin to decorrelate before observable specklereduction occurs. Speckle decorrelation, after appropriate motioncompensation, can be a sensitive measure of the mechanical disruption ofthe tissues, and thus a measure of therapeutic efficacy. This feedbackand monitoring technique may permit early observation of changesresulting from the acoustic cavitation/histotripsy process and canidentify changes in tissue before substantial or complete tissue effect(e.g., erosion occurs). In one embodiment, this method may be used tomonitor the acoustic cavitation/histotripsy process for enhanced drugdelivery where treatment sites/tissue is temporally disrupted, andtissue damage/erosion is not desired. In other embodiments, this maycomprise speckle decorrelation by movement of scatters in anincreasingly fluidized therapy volume. For example, in the case wherepartial or complete tissue erosion is desired.

For systems comprising feedback and monitoring via elastography, and asmeans of background, as treatment sites/tissue are further subdividedper an acoustic cavitation/histotripsy effect (homogenized, disrupted,or eroded), its mechanical properties change from a soft butinterconnected solid to a viscous fluid or paste with few long-rangeinteractions. These changes in mechanical properties can be measured byvarious imaging modalities including MRI and ultrasound imaging systems.For example, an ultrasound pulse can be used to produce a force (i.e., aradiation force) on a localized volume of tissue. The tissue response(displacements, strains, and velocities) can change significantly duringhistotripsy treatment allowing the state of tissue disruption to bedetermined by imaging or other quantitative means.

Systems may also comprise feedback and monitoring via shear wavepropagation changes. As means of background, the subdivision of tissuesmakes the tissue more fluid and less solid and fluid systems generallydo not propagate shear waves. Thus, the extent of tissue fluidizationprovides opportunities for feedback and monitoring of the histotripsyprocess. For example, ultrasound and MRI imaging systems can be used toobserve the propagation of shear waves. The extinction of such waves ina treated volume is used as a measure of tissue destruction ordisruption. In one system embodiment, the system and supportingsub-systems may be used to generate and measure the interacting shearwaves. For example, two adjacent ultrasound foci might perturb tissue bypushing it in certain ways. If adjacent foci are in a fluid, no shearwaves propagate to interact with each other. If the tissue is notfluidized, the interaction would be detected with external means, forexample, by a difference frequency only detected when two shear wavesinteract nonlinearly, with their disappearance correlated to tissuedamage. As such, the system may be configured to use this modality toenhance feedback and monitoring of the acoustic cavitation/histotripsyprocedure.

For systems comprising feedback and monitoring via acoustic emission,and as means of background, as a tissue volume is subdivided, its effecton acoustic cavitation/histotripsy (e.g., the bubble cloud here) ischanged. For example, bubbles may grow larger and have a differentlifetime and collapse changing characteristics in intact versusfluidized tissue. Bubbles may also move and interact after tissue issubdivided producing larger bubbles or cooperative interaction amongbubbles, all of which can result in changes in acoustic emission. Theseemissions can be heard during treatment and they change duringtreatment. Analysis of these changes, and their correlation totherapeutic efficacy, enables monitoring of the progress of therapy, andmay be configured as a feature of the system.

For systems comprising feedback and monitoring via electrical impedancetomography, and as means of background, an impedance map of a therapysite can be produced based upon the spatial electrical characteristicsthroughout the therapy site. Imaging of the conductivity or permittivityof the therapy site of a patient can be inferred from taking skinsurface electrical measurements. Conducting electrodes are attached to apatient's skin and small alternating currents are applied to some or allof the electrodes. One or more known currents are injected into thesurface and the voltage is measured at a number of points using theelectrodes. The process can be repeated for different configurations ofapplied current. The resolution of the resultant image can be adjustedby changing the number of electrodes employed. A measure of theelectrical properties of the therapy site within the skin surface can beobtained from the impedance map, and changes in and location of theacoustic cavitation/histotripsy (e.g., bubble cloud, specifically) andhistotripsy process can be monitored using this as configured in thesystem and supporting sub-systems.

The user may be allowed to further select, annotate, mark, highlight,and/or contour, various regions of interest or treatment sites, anddefined treatment targets (on the image(s)), of which may be used tocommand and direct the system where to image, test and/or treat, throughthe system software and user interfaces and displays. In somearrangements, the user may use a manual ultrasound probe (e.g.,diagnostic hand-held probe) to conduct the procedure. In anotherarrangement, the system may use a robot and/or electromechanicalpositioning system to conduct the procedure, as directed and/orautomated by the system, or conversely, the system can enablecombinations of manual and automated uses.

The system may further include the ability to conduct imageregistration, including imaging and image data set registration to allownavigation and localization of the system to the patient, including thetreatment site (e.g., tumor, critical structure, bony anatomy, anatomyand identifying features of, etc.). In one embodiment, the system allowsthe user to image and identify a region of interest, for example theliver, using integrated ultrasound, and to select and mark a tumor (orsurrogate marker of) comprised within the liver through/displayed in thesystem software, and wherein said system registers the image data to acoordinate system defined by the system, that further allows thesystem's Therapy and Robotics sub-systems to deliver synchronizedacoustic cavitation/histotripsy to said marked tumor. The system maycomprise the ability to register various image sets, including thosepreviously disclosed, to one another, as well as to afford navigationand localization (e.g., of a therapy transducer to a CT orMRI/ultrasound fusion image with the therapy transducer and Roboticssub-system tracking to said image).

The system may also comprise the ability to work in a variety ofinterventional, endoscopic and surgical environments, including aloneand with other systems (surgical/laparoscopic towers, vision systems,endoscope systems and towers, ultrasound enabled endoscopic ultrasound(flexible and rigid), percutaneous/endoscopic/laparoscopic and minimallyinvasive navigation systems (e.g., optical, electromagnetic,shape-sensing, ultrasound-enabled, etc.), of also which may work with,or comprise various optical imaging capabilities (e.g., fiber and ordigital). The disclosed system may be configured to work with thesesystems, in some embodiments working alongside them in concert, or inother embodiments where all or some of the system may be integrated intothe above systems/platforms (e.g., acousticcavitation/histotripsy-enabled endoscope system or laparoscopic surgicalrobot). In many of these environments, a therapy transducer may beutilized at or around the time of use, for example, of an opticallyguided endoscope/bronchoscope, or as another example, at the time alaparoscopic robot (e.g., Intuitive Da Vinci* Xi system) isviewing/manipulating a tissue/treatment site. Further, these embodimentsand examples may include where said other systems/platforms are used todeliver (locally) fluid to enable the creation of a man-made acousticwindow, where on under normal circumstances may not exist (e.g.,fluidizing a segment or lobe of the lung in preparation for acousticcavitation/histotripsy via non-invasive transthoracic treatment (e.g.,transducer externally placed on/around patient). Systems disclosedherein may also comprise all or some of their sub-system hardwarepackaged within the other system cart/console/systems described here(e.g., acoustic cavitation/histotripsy system and/or sub-systemsintegrated and operated from said navigation or laparoscopic system).

The system may also be configured, through various aforementionedparameters and other parameters, to display real-time visualization of abubble cloud in a spatial-temporal manner, including the resultingtissue effect peri/post-treatment from tissue/bubble cloud interaction,wherein the system can dynamically image and visualize, and display, thebubble cloud, and any changes to it (e.g., decreasing or increasingechogenicity), which may include intensity, shape, size, location,morphology, persistence, etc. These features may allow users tocontinuously track and follow the treatment in real-time in oneintegrated procedure and interface/system, and confirm treatment safetyand efficacy on the fly (versus other interventional or surgicalmodalities, which either require multiple procedures to achieve thesame, or where the treatment effect is not visible in real-time (e.g.,radiation therapy), or where it is not possible to achieve such (e.g.,real-time visualization of local tissue during thermal ablation), and/orwhere the other procedure further require invasive approaches (e.g.,incisions or punctures) and iterative imaging in a scanner betweenprocedure steps (e.g., CT or MRI scanning). The above disclosed systems,sub-systems, components, modalities, features and work-flows/methods ofuse may be implemented in an unlimited fashion through enablinghardware, software, user interfaces and use environments, and futureimprovements, enhancements and inventions in this area are considered asincluded in the scope of this disclosure, as well as any of theresulting data and means of using said data for analytics, artificialintelligence or digital health applications and systems.

Robotics

They system may comprise various Robotic sub-systems and components,including but not limited to, one or more robotic arms and controllers,which may further work with other sub-systems or components of thesystem to deliver and monitor acoustic cavitation/histotripsy. Aspreviously discussed herein, robotic arms and control systems may beintegrated into one or more Cart configurations.

For example, one system embodiment may comprise a Cart with anintegrated robotic arm and control system, and Therapy, IntegratedImaging and Software, where the robotic arm and other listed sub-systemsare controlled by the user through the form factor of a single bedsideCart.

In other embodiments, the Robotic sub-system may be configured in one ormore separate Carts, that may be a driven in a master/slaveconfiguration from a separate master or Cart, wherein therobotically-enabled Cart is positioned bed/patient-side, and the Masteris at a distance from said Cart.

Disclosed robotic arms may be comprised of a plurality of joints,segments, and degrees of freedom and may also include various integratedsensor types and encoders, implemented for various use and safetyfeatures. Sensing technologies and data may comprise, as an example,vision, potentiometers, position/localization, kinematics, force,torque, speed, acceleration, dynamic loading, and/or others. In somecases, sensors may be used for users to direct robot commands (e.g.,hand gesture the robot into a preferred set up position, or to dockhome). Additional details on robotic arms can be found in US Patent Pub.No. 2013/0255426 to Kassow et al. which is disclosed herein by referencein its entirety.

The robotic arm receives control signals and commands from the roboticcontrol system, which may be housed in a Cart. The system may beconfigured to provide various functionalities, including but not limitedto, position, tracking, patterns, triggering, and events/actions.

Position may be configured to comprise fixed positions, palletpositions, time-controlled positions, distance-controlled positions,variable-time controlled positions, variable-distance controlledpositions.

Tracking may be configured to comprise time-controlled tracking and/ordistance-controlled tracking.

The patterns of movement may be configured to comprise intermediatepositions or waypoints, as well as sequence of positions, through adefined path in space.

Triggers may be configured to comprise distance measuring means, time,and/or various sensor means including those disclosed herein, and notlimited to, visual/imaging-based, force, torque, localization,energy/power feedback and/or others.

Events/actions may be configured to comprise various examples, includingproximity-based (approaching/departing a target object), activation orde-activation of various end-effectors (e.g., therapy transducers),starting/stopping/pausing sequences of said events, triggering orswitching between triggers of events/actions, initiating patterns ofmovement and changing/toggling between patterns of movement, and/ortime-based and temporal over the defined work and time-space.

In one embodiment, the system comprises a three degree of freedomrobotic positioning system, enabled to allow the user (through thesoftware of the system and related user interfaces), to micro-position atherapy transducer through X, Y, and Z coordinate system, and wheregross macro-positioning of the transducer (e.g., aligning the transduceron the patient's body) is completed manually. In some embodiments, therobot may comprise 6 degrees of freedom including X, Y, Z, and pitch,roll and yaw. In other embodiments, the Robotic sub-system may comprisefurther degrees of freedom, that allow the robot arm supporting base tobe positioned along a linear axis running parallel to the generaldirection of the patient surface, and/or the supporting base height tobe adjusted up or down, allowing the position of the robotic arm to bemodified relative to the patient, patient surface, Cart, Couplingsub-system, additional robots/robotic arms and/or additional surgicalsystems, including but not limited to, surgical towers, imaging systems,endoscopic/laparoscopic systems, and/or other.

One or more robotic arms may also comprise various features to assist inmaneuvering and modifying the arm position, manually or semi-manually,and of which said features may interface on or between the therapytransducer and the most distal joint of the robotic arm. In someembodiments, the feature is configured to comprise a handle allowingmaneuvering and manual control with one or more hands. The handle mayalso be configured to include user input and electronic control featuresof the robotic arm, to command various drive capabilities or modes, toactuate the robot to assist in gross or fine positioning of the arm(e.g., activating or deactivating free drive mode). The work-flow forthe initial positioning of the robotic arm and therapy head can beconfigured to allow either first positioning the therapy transducer/headin the coupling solution, with the therapy transducer directlyinterfaced to the arm, or in a different work-flow, allowing the user toset up the coupling solution first, and enabling the robot arm to beinterfaced to the therapy transducer/coupling solution as alater/terminal set up step.

In some embodiments, the robotic arm may comprise a robotic arm on alaparoscopic, single port, endoscopic, hybrid or combination of, and/orother robot, wherein said robot of the system may be a slave to a masterthat controls said arm, as well as potentially a plurality of otherarms, equipped to concurrently execute other tasks (vision, imaging,grasping, cutting, ligating, sealing, closing, stapling, ablating,suturing, marking, etc.), including actuating one or more laparoscopicarms (and instruments) and various histotripsy system components. Forexample, a laparoscopic robot may be utilized to prepare the surgicalsite, including manipulating organ position to provide more idealacoustic access and further stabilizing said organ in some cases tominimize respiratory motion. In conjunction and parallel to this, asecond robotic arm may be used to deliver non-invasive acousticcavitation through a body cavity, as observed under real-time imagingfrom the therapy transducer (e.g., ultrasound) and with concurrentvisualization via a laparoscopic camera. In other related aspects, asimilar approach may be utilized with a combination of an endoscopic andnon-invasive approach, and further, with a combination of an endoscopic,laparoscopic and non-invasive approach.

Coupling

Systems may comprise a variety of Coupling sub-system embodiments, ofwhich are enabled and configured to allow acoustic coupling to thepatient to afford effective acoustic cavitation/histotripsy (e.g.,provide acoustic medium between transducer and patient, and support of).These may include different form factors of such, including open andenclosed solutions, and some arrangements which may be configured toallow dynamic control over the acoustic medium (e.g., temperature,dissolved gas content, level of particulate filtration, sterility,etc.). Such dynamic control components may be directly integrated to thesystem (within the Cart), or may be in communication with the system,but externally situated.

The Coupling sub-system typically comprises, at a minimum, couplingmedium, a reservoir/container to contain said coupling medium, and asupport structure. In most embodiments, the coupling medium is water,and wherein the water may be conditioned before or during the procedure(e.g., chilled, degassed, filtered, etc.). Various conditioningparameters may be employed based on the configuration of the system andit's intended use/application.

The reservoir or medium container may be formed and shaped toadapt/conform to the patient, allow the therapy transducer to engage andwork within the acoustic medium, per defined and required working space(minimum volume of medium to allow the therapy transducer to bepositioned and/or move through one or more treatment positions orpatterns, and at various standoffs or depths from the patient, etc.),and wherein said reservoir or medium container may also mechanicallysupport the load, and distribution of the load, through the use of amechanical and/or electromechanical support structure. The container maybe of various shapes, sizes, curvatures, and dimensions, and may becomprised of a variety of materials (single, multiple, composites,etc.), of which may vary throughout. In some embodiments, it maycomprise features such as films, drapes, membranes, bellows, etc. thatmay be insertable and removable, and/or fabricated within. It mayfurther contain various sensors, drains, lighting (e.g., LEDs),markings, text, etc.

In one embodiment, the reservoir or medium container contains a sealableframe, of which a membrane and/or film may be positioned within, toafford a conformable means of contacting the reservoir (later comprisingthe therapy transducer) as an interface to the patient, that furtherprovides a barrier to the medium (e.g., water) between the patient andtransducer). In other embodiments, the membrane and/or film may comprisean opening, the edge of which affords mechanical sealing to the patient,but in contrast allows medium communication with the patient (e.g.,direct water interface with patient). The superstructure of thereservoir or medium container in both these examples may further affordthe proximal portion of the structure (e.g., top) to be open or enclosed(e.g., to prevent spillage or afford additional features).

Disclosed membranes may be comprised of various elastomers, viscoelasticpolymers, thermoplastics, thermoplastic elastomers, thermoset polymers,silicones, urethanes, rigid/flexible co-polymers, block co-polymers,random block co-polymers, etc. Materials may be hydrophilic,hydrophobic, surface modified, coated, extracted, etc., and may alsocontain various additives to enhance performance, appearance orstability. In some embodiments, the thermoplastic elastomer may bestyrene-ethylene-butylene-styrene (SEBS), or other like strong andflexible elastomers.

Said materials may be formed into useful membranes through molding,casting, spraying, ultrasonic spraying and/or any other processingmethodology that produces useful embodiments. They may be single use orreposable/reusable. They may be provided non-sterile, asepticallycleaned or sterile, where sterilization may comprise any known method,including but not limited to ethylene oxide, gamma, e-beam, autoclaving,steam, peroxide, plasma, chemical, etc. Membranes can be furtherconfigured with an outer molded frame to provide mechanical stabilityduring assembly of the coupling sub-system. Various parameters of themembrane can be optimized for this method of use, including thickness,thickness profile, density, formulation (e.g. polymer molecular weightand copolymer ratios), including optimizing specifically to maximizeacoustic properties, including minimizing impact to cavitationinitiation threshold values, and/or ultrasound imaging artifacts,including but not limited to membrane reflections.

Open reservoirs or medium containers may comprise various methods offilling, including using pre-prepared medium or water, that may bedelivered into the such, in some cases to a defined specification ofwater (level of temperature and gas saturation, etc.), or they maycomprise additional features integral to the design that allow fillingand draining (e.g., ports, valves, hoses, tubing, fittings, bags, pumps,etc.).

Enclosed iterations of the reservoir or medium container may comprisevarious features for sealing, in some embodiments sealing to aproximal/top portion or structure of a reservoir/container, or in othercases where sealing may comprise embodiments that seal to thetransducer, or a feature on the transducer housings. Further, someembodiments may comprise the dynamic ability to control the volume offluid within these designs, to minimize the potential for air bubbles orturbulence in said fluid. As such, integrated features allowing fluidcommunication, and control of, may be provided (ability toprovide/remove fluid on demand), including the ability to monitor andcontrol various fluid parameters, some disclosed above. In order toprovide this functionality, the overall system, and as part, theCoupling sub-system, may comprise a fluid conditioning system, which maycontain various electromechanical devices, systems, power, sensing,computing and control systems, etc.

Coupling support systems may include various mechanical support devicesto interface the reservoir/container and medium to the patient, and theworkspace (e.g., bed). In some embodiments, the support system comprisesa mechanical arm with 3 or more degrees of freedom. Said arm mayinterface with one or more locations (and features) of the bed,including but not limited to, the frame, rails, customized rails orinserts, as well as one or more locations of the reservoir or container.The arm may be a feature implemented on one or more Carts, wherein Cartsmay be configured in various unlimited permutations, in some cases wherea Cart only comprises the role of supporting and providing the disclosedsupport structure.

In some embodiments, the support structure and arm may be arobotically-enabled arm, implemented as a stand-alone Cart, orintegrated into a Cart further comprising two or more systemsub-systems, or where in the robotically-enabled arm is an arm ofanother robot, of interventional, surgical or other type, and mayfurther comprise various user input features to actuate/control therobotic arm (e.g., positioning into/within coupling medium) and/orCoupling solution features (e.g., filling, draining, etc.).

Software

The system may comprise various software applications, features andcomponents which allow the user to interact, control and use the systemfor a plethora of clinical applications. The Software may communicateand work with one or more of the sub-systems, including but not limitedto Therapy, Integrated Imaging, Robotics and Other Components,Ancillaries and Accessories of the system.

Overall, in no specific order of importance, the software may providefeatures and support to initialize and set up the system, service thesystem, communicate and import/export/store data,modify/manipulate/configure/control/command various settings andparameters by the user, mitigate safety and use-related risks, planprocedures, provide support to various configurations of transducers,robotic arms and drive systems, function generators and amplifiercircuits/slaves, test and treatment ultrasound sequences, transducersteering and positioning (electromechanical and electronic beamsteering, etc.), treatment patterns, support for imaging and imagingprobes, manual and electromechanical/robotically-enabling movement of,imaging support for measuring/characterizing various dimensions withinor around procedure and treatment sites (e.g., depth from one anatomicallocation to another, etc., pre-treatment assessments and protocols formeasuring/characterizing in situ treatment site properties andconditions (e.g., acoustic cavitation/histotripsy thresholds andheterogeneity of), targeting and target alignment, calibration,marking/annotating, localizing/navigating, registering, guiding,providing and guiding through work-flows, procedure steps, executingtreatment plans and protocols autonomously, autonomously and while underdirect observation and viewing with real-time imaging as displayedthrough the software, including various views and viewports for viewing,communication tools (video, audio, sharing, etc.), troubleshooting,providing directions, warnings, alerts, and/or allowing communicationthrough various networking devices and protocols. It is furtherenvisioned that the software user interfaces and supporting displays maycomprise various buttons, commands, icons, graphics, text, etc., thatallow the user to interact with the system in a user-friendly andeffective manner, and these may be presented in an unlimited number ofpermutations, layouts and designs, and displayed in similar or differentmanners or feature sets for systems that may comprise more than onedisplay (e.g., touch screen monitor and touch pad), and/or may networkto one or more external displays or systems (e.g., another robot,navigation system, system tower, console, monitor, touch display, mobiledevice, tablet, etc.).

The software, as a part of a representative system, including one ormore computer processors, may support the various aforementionedfunction generators (e.g., FPGA), amplifiers, power supplies and therapytransducers. The software may be configured to allow users to select,determine and monitor various parameters and settings for acousticcavitation/histotripsy, and upon observing/receiving feedback onperformance and conditions, may allow the user to stop/start/modify saidparameters and settings.

The software may be configured to allow users to select from a list ormenu of multiple transducers and support the auto-detection of saidtransducers upon connection to the system (and verification of theappropriate sequence and parameter settings based on selectedapplication). In other embodiments, the software may update thetargeting and amplifier settings (e.g., channels) based on the specifictransducer selection. The software may also provide transducerrecommendations based on pre-treatment and planning inputs. Conversely,the software may provide error messages or warnings to the user if saidtherapy transducer, amplifier and/or function generator selections orparameters are erroneous, yield a fault or failure. This may furthercomprise reporting the details and location of such.

In addition to above, the software may be configured to allow users toselect treatment sequences and protocols from a list or menu, and tostore selected and/or previous selected sequences and protocols asassociated with specific clinical uses or patient profiles. Relatedprofiles may comprise any associated patient, procedure, clinical and/orengineering data, and maybe used to inform, modify and/or guide currentor future treatments or procedures/interventions, whether as decisionsupport or an active part of a procedure itself (e.g., using serial datasets to build and guide new treatments).

As a part of planning or during the treatment, the software (and inworking with other components of the system) may allow the user toevaluate and test acoustic cavitation/histotripsy thresholds at variouslocations in a user-selected region of interest or defined treatmentarea/volume, to determine the minimum cavitation thresholds throughoutsaid region or area/volume, to ensure treatment parameters are optimizedto achieve, maintain and dynamically control acousticcavitation/histotripsy. In one embodiment, the system allows a user tomanually evaluate and test threshold parameters at various points. Saidpoints may include those at defined boundary, interior to the boundaryand center locations/positions, of the selected region of interest andtreatment area/volume, and where resulting threshold measurements may bereported/displayed to the user, as well as utilized to update therapyparameters before treatment. In another embodiment, the system may beconfigured to allow automated threshold measurements and updates, asenabled by the aforementioned Robotics sub-system, wherein the user maydirect the robot, or the robot may be commanded to execute themeasurements autonomously.

Software may also be configured, by working with computer processors andone or more function generators, amplifiers and therapy transducers, toallow various permutations of delivering and positioning optimizedacoustic cavitation/histotripsy in and through a selected area/volume.This may include, but not limited to, systems configured with afixed/natural focus arrangement using purely electromechanicalpositioning configuration(s), electronic beam steering (with or withoutelectromechanical positioning), electronic beam steering to a newselected fixed focus with further electromechanical positioning, axial(Z axis) electronic beam steering with lateral (X and Y)electromechanical positioning, high speed axial electronic beam steeringwith lateral electromechanical positioning, high speed beam steering in3D space, various combinations of including with dynamically varying oneor more acoustic cavitation/histotripsy parameters based on theaforementioned ability to update treatment parameters based on thresholdmeasurements (e.g., dynamically adjusting amplitude across the treatmentarea/volume).

Other Components, Ancillaries and Accessories

The system may comprise various other components, ancillaries andaccessories, including but not limited to computers, computerprocessors, power supplies including high voltage power supplies,controllers, cables, connectors, networking devices, softwareapplications for security, communication, integration into informationsystems including hospital information systems, cellular communicationdevices and modems, handheld wired or wireless controllers, goggles orglasses for advanced visualization, augmented or virtual realityapplications, cameras, sensors, tablets, smart devices, phones, internetof things enabling capabilities, specialized use “apps” or user trainingmaterials and applications (software or paper based), virtual proctorsor trainers and/or other enabling features, devices, systems orapplications, and/or methods of using the above.

System Variations and Methods/Applications

In addition to performing a breadth of procedures, the system may allowadditional benefits, such as enhanced planning, imaging and guidance toassist the user. In one embodiment, the system may allow a user tocreate a patient, target and application specific treatment plan,wherein the system may be configured to optimize treatment parametersbased on feedback to the system during planning, and where planning mayfurther comprise the ability to run various test protocols to gatherspecific inputs to the system and plan.

Feedback may include various energy, power, location, position, tissueand/or other parameters.

The system, and the above feedback, may also be further configured andused to autonomously (and robotically) execute the delivery of the testprotocols and optimized treatment plan and protocol, as visualized underreal-time imaging during the procedure, allowing the user to directlyobserve the local treatment tissue effect, as it progresses throughtreatment, and start/stop/modify treatment at their discretion. Bothtest and treatment protocols may be updated over the course of theprocedure at the direction of the user, or in some embodiments, based onlogic embedded within the system.

It is also recognized that many of these benefits may further improveother forms of acoustic therapy, including thermal ablation with highintensity focused ultrasound (HIFU), high intensity therapeuticultrasound (HITU) including boiling histotripsy (thermal cavitation),and are considered as part of this disclosure.

In another aspect, the Therapy sub-system, comprising in part, one ormore amplifiers, transducers and power supplies, may be configured toallow multiple acoustic cavitation and histotripsy driving capabilities,affording specific benefits based on application, method and/or patientspecific use. These benefits may include, but are not limited to, theability to better optimize and control treatment parameters, which mayallow delivery of more energy, with more desirable thermal profiles,increased treatment speed and reduced procedure times, enable electronicbeam steering and/or other features.

This disclosure also includes novel systems and concepts as related tosystems and sub-systems comprising new and “universal” amplifiers, whichmay allow multiple driving approaches (e.g., single and multi-cyclepulsing). In some embodiments, this may include various novel featuresto further protect the system and user, in terms of electrical safety orother hazards (e.g., damage to transducer and/or amplifier circuitry).

In another aspect, the system, and Therapy sub-system, may include aplethora of therapy transducers, where said therapy transducers areconfigured for specific applications and uses and may accommodatetreating over a wide range of working parameters (target size, depth,location, etc.) and may comprise a wide range of working specifications(detailed below). Transducers may further adapt, interface and connectto a robotically-enabled system, as well as the Coupling sub-system,allowing the transducer to be positioned within, or along with, anacoustic coupling device allowing, in many embodiments, concurrentimaging and histotripsy treatments through an acceptable acousticwindow. The therapy transducer may also comprise an integrated imagingprobe or localization sensors, capable of displaying and determiningtransducer position within the treatment site and affording a directfield of view (or representation of) the treatment site, and as theacoustic cavitation/histotripsy tissue effect and bubble cloud may ormay not change in appearance and intensity, throughout the treatment,and as a function of its location within said treatment (e.g., tumor,healthy tissue surrounding, critical structures, adipose tissue, etc.).

The systems, methods and use of the system disclosed herein, may bebeneficial to overcoming significant unmet needs in the areas of softtissue ablation, oncology, immuno-oncology, advanced image guidedprocedures, surgical procedures including but not limited to open,laparoscopic, single incision, natural orifice, endoscopic,non-invasive, various combination of, various interventional spaces forcatheter-based procedures of the vascular, cardiovascular and/orneuro-related spaces, cosmetics/aesthetics, metabolic (e.g., type 2diabetes), plastics and reconstructive, ocular and ophthalmology,gynecology and men's health, and other systems, devices and methods oftreating diseased, injured, undesired, or healthy tissues, organs orcells.

Treatment Patterns

Systems and methods are also provided for improving treatment patternswithin tissue that can reduce treatment time, improve efficacy, andreduce the amount of energy and prefocal tissue heating delivered topatients. In some embodiments, the treatment patterns describe the wayin which the bubble cloud is moved or manipulated within a target tissuevolume to ablate the tissue volume.

A “Standard Z” (SZ) pattern is the treatment path that traverses thespherical volume in a series of axial slices (parallel to the imagingplane), beginning with the center slice and progressing outward in thepositive x-dimension until the entire +x-half of the sphere is treated.The treatment then moves to the untreated slice adjacent to the centerand treats the remaining half of the spherical volume in an analogousmanner, in this case progressing outward in the negative x-dimension.Within each slice, treatment starts at the center point and movesoutward in a spiraling fashion.

The “Top-Down” and “Bottom-Up” patterns differ from the SZ pattern inthat they do not traverse the volume in axial slices; rather, theyprogress through the sphere in a series of lateral slices (i.e. slicesperpendicular to the acoustic axis of the therapy transducer). Withineach slice, treatment starts at the center point and moves outward in aspiraling fashion (identical to the manner in which the SZ patterntraverses an axial slice). As the names imply, the “Top-Down” and“Bottom-Up” patterns progress through the lateral planes of the spherefrom the upper-most (closest to the transducer) to the distal-most(farthest from the transducer) or distal-most to upper-most,respectively.

FIGS. 7A-7B provide illustrations of a “DZ” pattern. The target tissuevolume is divided into a number of slices (e.g., 13 slices in theexample shown in FIG. 7A), which are treated in alternating orderstarting from the middle of the volume (number below each sliceindicates treatment order). Within each slice, as shown in FIG. 7B,columns are treated in an alternating fashion (number below each columnindicates treatment order). The columns themselves can be traversed in atop-down or a bottom-up manner, depending on the treatment type, tissue,type, and tissue location.

The “Standard Z Side-Side” and “Standard Z Shuffle” patterns representvariations of the SZ pattern. The spherical volume is still traversed ina set of axial slices parallel to the imaging plane, and the progressionof treatment within each slice remains the same. Only the order in whichthe axial slices are treated is varied in these two schemes.Specifically, the “Standard Z Side-Side” pattern treats the axial slicesstarting at one lateral extreme of the volume (e.g. the slice farthestin the +x-dimension) and progresses through slices one at a time untilreaching the other lateral extreme of the volume (the slice farthest inthe −x-dimension). The “Standard Z Shuffle” pattern increments throughslices in a strategic order selected to maximize the spatialdistribution of successive treatment slices. If the center axial sliceof the sphere is defined as slice 0, the slice farthest in the+x-dimension as 6, and the slice farthest in the −x-dimension as −6,then the “Standard Z Shuffle” progresses through the 13 slicescomprising the 3 cm sphere in the following order: 0, 4, −2, −5, −1, 6,−3, 5, 1, −6, 3, −4, 2.

The “Spiral In-Out” pattern traverses the spherical volume in a seriesof radial layers, from the center of the sphere outward. Within eachlayer, and when transitioning between layers, the points are treated inorder of proximity (i.e. the next treatment point is the closestuntreated point in the current radial layer, or the closest point in thenext radial layer when transitioning between layers).

In one example, histotripsy therapy can be applied in a “bubble saber”or column shape. The “bubble saber” or column shape can be implementedby rapidly electronically steering the bubble cloud focus in thez-direction through a column of treatment points, and repeating thecolumn treatment multiple times, thereby removing the need tomechanically move the bubble cloud in the z-direction. The “bubblesaber” technique can provide a large thermal benefit to byelectronically steering the bubble cloud to a more proximal locationthan the geometric focus to ablate shallower targets. The primarythermal benefit of the “bubble saber” technique comes from theelectronic steering itself (utilization of the lowest possible effectivef number). Another benefit of the “bubble saber” is the reduced impactof motion on local dose, and the potential efficacy benefits of a moreparallel treatment strategy (some protection against intact “chunks” oftissue moving to a previously treated area and escaping furthertreatment). FIGS. 8-9 illustrate examples of a column shaped bubblecloud, illuminated by a laser in FIG. 8 and shown under real-timeultrasound imaging in FIG. 9 (an optical image is shown in FIG. 9 , butit should be understood that real-time imaging such as ultrasound canalso be used).

In another embodiment, histotripsy therapy can be applied in a “radialspiral” pattern that minimizes the distance between treatment columnswhile maintaining an “inside-out” lesion development in tissue. Insteadof columns of treatment points arranged in a cartesian grid oflocations, the treatment points in this technique are arranged in radiallayers. These layers are then treated from inside out, with columnswithin each layer treated sequentially around each ring in a spiral (oralternating from side to side if preserving the thermal benefit ofsequential treatment columns being are distant as possible is required).This pattern, illustrated in FIG. 11A, provides a more consistent cloudoverlap in three-dimensions and minimized the distance betweensuccessive treatment columns compared to a rectilinear treatment pattern(as illustrated in FIG. 10 ), resulting in a planned ablation volumethat more closely matches ellipsoidal planning contours.

The radial spiral technique allows the flexibility to reduce treatmenttimes by removing the de facto cooling time when moving betweenspatially distant treatment columns. It is important to note though thatthis pattern does not remove the need for this cooling time, it onlyallows the flexibility to include or exclude cooling time only asrequired by the anticipated thermal load, i.e., the option to go fasterif thermally tolerable.

FIGS. 11B and 11C illustrate additional side and top views of a radialspiral pattern, showing how each of the individual planned bubble cloudtreatments fills the target tissue volume. It can be seen from theseimages that the radial spiral pattern covers nearly the entire tissuevolume. In some embodiments, the radial spiral pattern can beimplemented to cover 90-100% of the target tissue volume. Ablationcenter points for each bubble cloud are distributed at discrete spacingin X and Y, with any points outside the tissue volume boundarydiscarded. Point positions in Z are dynamically adjusted to match thetissue volume boundary contour.

FIGS. 11D-11E show another implementation of a radial spiral pattern. Inthis example, ablation center points for each bubble cloud aredistributed in radial layers in X and Y, with radii dynamically adjustedto match the target tissue volume boundaries. Point positions in Z arealso dynamically adjusted to match the target tissue volume boundarycontours. Column treatment strategy is preserved, with no significantgaps between treatment ellipsoids and the target tissue volume contoursin any dimension. In some embodiments, this radial spiral pattern can beimplemented to cover 95-100% of the target tissue volume.

Threshold Testing

As described above, the systems described herein include the capabilityto evaluate and test acoustic cavitation/histotripsy thresholds atvarious locations in a user-selected region of interest or definedtreatment area/volume, to determine the minimum cavitation thresholdsthroughout said region or area/volume, to ensure treatment parametersare optimized to achieve, maintain and dynamically control acousticcavitation/histotripsy. During treatment planning or during therapy,cavitation threshold test pulses can be transmitted into a plurality oflocations of interest. The number of test locations of interest can bechosen based on the size and/or shape of the treatment region. Forexample, a spherical treatment region benefits from at least seven testlocations to probe the extremes of the spherical volume. FIG. 12 is anillustration of one example of using seven test pulse locations within aspherical treatment volume. In this illustrated example, the testprotocol and test pulses can be positioned at 1) the center of thetreatment volume, 2) the proximal-most aspect of the treatment volume(top), 3) the distal-most aspect of the treatment volume, 4) theleft-most aspect of the treatment volume, 5) the right-most aspect ofthe treatment volume, 6) the cranial-most aspect of the treatment volume(head), and 7) the caudal-most aspect of the treatment volume (tail).

During therapy, the cavitation threshold at each of the locations ofinterest can be evaluated with a single therapy PRF to determine ifcavitation has formed before incrementing to the next PRF. For example,the formation (or not) of cavitation can be observed in real-time withimaging such as ultrasound imaging. In general, the driving voltagerequired to initiate a vigorous bubble cloud in tissue decreases as thetherapy PRF increases. The cavitation threshold in the tissue can alsovary as a treatment procedure progresses. Thus, testing various pointsof interest within a treatment volume during treatment can be a usefultool to evaluate the cavitation threshold(s) in real-time and adjust thePRF and/or driving voltage of the therapy pulses to optimize treatmentat each of the tested locations. The treatment protocol itself can thenbe adjusted based on the test pulses to utilize variable amplitudes/PRFbased on the test results to ensure the optimal amount of energy isdelivered into each location of the tissue for histotripsy therapy.Additionally, the depth at each of the test locations can be measured ordetermined (either manually or automatically with the system) to provideadditional information to the system for determining optimal treatmentparameters.

In some embodiments, the test locations can be used to determine amaximum amount of energy that may be applied without generatingundesired damage to the test location or surround or interveningtissues. For example, while determining the cavitation thresholds ateach of the test locations, the drive voltage and/or PRF of the systemcan be increased until cavitation is observed under real-time imaging.In some embodiments, the drive voltage and/or PRF can be increased untilundesirable damage to the test location or cavitation/thermal damage toother locations outside of the test location are observed. This can beused to determine the maximum amount of energy that can be applied for agiven test location.

Based on the test protocol and tested cavitation thresholds, theappropriate driving voltage for each point in the treatment grid can bechosen. With the required voltage at the center and six extremes of thetarget volume serving as inputs, the voltages for the remaining pointscomprising the treatment volume can be interpolated. The driving voltagecan then be adjusted automatically by the software as the therapyprogresses through the automated treatment volume. In this way eachpoint is ablated using an amplitude sufficient to maintain anefficacious bubble cloud, but not overly so in order to minimize thethermal deposition in the acoustic path.

For example, a method of delivering histotripsy therapy to tissue cancomprise delivering histotripsy pulses into tissue at a plurality oftarget test locations and imaging the test location in real-time toevaluate whether cavitation has formed at the test locations. Ifcavitation has not formed at the test locations, the driving voltageand/or the PRF of the histotripsy pulses can be adjusted, andhistotripsy pulses with the adjusted parameters can be delivered intothe tissue at the test locations. Real-time imaging can again be used toevaluate whether cavitation has formed at each test location. Thisprocess can be repeated until the cavitation threshold at each testlocation is determined, and a high-density map can be created based onvarious algorithms to extrapolate thresholds across the targeted regionof interest/treatment volume, specific to the acoustic pathway andtarget depth. For example, if cavitation thresholds are known at a firsttest location and a second test location, then the cavitation thresholdat a third test location can be extrapolated based on the cavitationthresholds of the first and second test locations. This extrapolationcan be further based on the tissue type, target tissue depth, andacoustic pathway of the third test location.

In one example, a method of treating tissue can comprise transmittingultrasound pulses into a first test location with at least oneultrasound transducer, determining a first cavitation threshold at thefirst test location, transmitting ultrasound pulses into a second testlocation with the at least one ultrasound transducer, determining asecond cavitation threshold at the second test location, adjusting afirst driving voltage and/or PRF of the at least one transducer based onthe first cavitation threshold, transmitting ultrasound pulses into thefirst test location with the at least one ultrasound transducer at thefirst adjusted driving voltage and/or PRF to generate cavitation at thefirst test location, adjusting a second driving voltage and/or PRF ofthe at least one transducer based on the second cavitation threshold,and transmitting ultrasound pulses into the second test location withthe at least one ultrasound transducer at the second adjusted drivingvoltage and/or PRF to generate cavitation at the second test location.

Treatment Pulse Sequences and Thermal Management

A given Histotripsy therapy or treatment session can be defined in termsof a set number of pulses N that are to be delivered over a set totaltreatment time T. The number of pulses delivered every second by thesystems described herein is defined by the pulse repetition frequency(PRF) of the system, which can be adjusted during therapy depending onthe cavitation threshold, the tissue type, depth, etc. Thus, the totalnumber of pulses N delivered over the total treatment time T (inseconds) is equal to the total treatment time T multiplied by the PRF ofthe system. For example, a system operating at a constant 200 Hz PRF fora total treatment time of 10 minutes (600 seconds) will have a totalnumber of pulses N equal to 120,000. The systems and methods describedherein can include PRF's of 400 Hz or greater to generate acousticcavitation, including PRF's ranging from 400 to 900 Hz.

Systems and methods are provided herein that implement Histotripsy pulsesequences with frequent short cooling periods that advantageouslyimprove the thermal profile generated by histotripsy treatment, with thelimiting case of N pulses equally distributed over the treatment time Tyielding the minimum temperature rise. These pulse sequences can furtherbe characterized in terms of the amount of time in which therapy isactively delivered to tissue relative to the amount of cooling time inwhich no therapy pulses are delivered to tissue. For example, a systemdelivering therapy pulses at a 400 Hz PRF for 5 minutes, followed by a 5minute cooling time in which no therapy pulses are delivered (for atotal treatment time of 10 minutes) would have a ratio of therapy (5minutes) to cooling (5 minutes) of 1:1.

FIG. 13A illustrates temperature profiles resulting from six pulseschemes, while the corresponding t43 curves are shown in FIG. 13B. Thepulse schemes illustrated comprise the following over a total treatmenttime of 10 minutes:

Scheme 1301: 200 Hz PRF for 10 minutes.

Scheme 1302: 400 Hz PRF for 5 minutes, followed by a 5 minute coolingtime

Scheme 1303: 400 Hz PRF for 2.5 minutes, followed by 2.5 minutes ofcooling with therapy and cooling repeated until total treatment time of10 minutes is achieved.

Scheme 1304: 400 Hz PRF for 1.25 minutes, followed by 1.25 minutes ofcooling with therapy and cooling repeated until total treatment time of10 minutes is achieved.

Scheme 1305: 800 Hz for 1.25 minutes, followed by 3.75 minutes ofcooling with therapy and cooling repeated until total treatment time of10 minutes is achieved.

Scheme 1306: 266.67 Hz for 3.75 minutes, followed by 1.25 minutes ofcooling with therapy and cooling repeated until total treatment time of10 minutes is achieved.

As shown in FIG. 13A, the lowest temperature rise is produced when the120,000 histotripsy pulses are equally distributed over the 10 minutetotal treatment time window (Scheme 1301).

When the therapy PRF is doubled and cooling steps are imposed (Schemes1302-1304), the extent of the temperature rise is dependent on thedistribution of cooling steps. A single long cooling step (Scheme 1302)results in the greatest temperature rise observed with this strategy.Conversely, shorter/more frequent cooling steps (Scheme 1304) moreclosely approximate the case of equally distributed pulses and result inthe lowest temperature rise observed with this strategy.

Finally, Schemes 1305 and 1306 indicate that, for a set number ofhistotripsy pulses delivered within a given total treatment time window,a higher therapy:cooling time ratio (e.g. 3:1) is advantageous to alower therapy:cooling time ratio (e.g. 1:3). Essentially, for a setnumber of histotripsy pulses delivered within a given time window, alower PRF is thermally beneficial. This is consistent with the result ofScheme 1301, which indicates that the lowest possible PRF (achieved byuniformly distributing the histotripsy pulses within the given timewindow) produces the lowest temperature rise.

When Histotripsy is used to ablate a target volume larger than thecavitation bubble clouds created by the system, the cavitation focus ofthe Histotripsy therapy system is moved (mechanically or electronically)within the target volume to ablate the entire target volume. Thisdisclosure provides methods and techniques that can improve the thermalprofile of Histotripsy therapy when ablating a target tissue volumelarger than the cavitation bubble cloud.

TABLE 1 Bubble # Therapy Therapy Manipulation Pulses: Total SequencePulse (BM) Pulse # BM Pulses Treatment Strategy PRF (Hz) PRF (Hz)(Ratio) Time (min) 1401 300 2400 1:7 24 1402 240 2400 1:9 30 1403 150600 1:3 2 × 24 1404 150 600 1:3 48 1405 162 648 1:3 45

Table 1 describes a series of pulse sequence strategies including thePRF of the therapy pulse and the PRF of the bubble manipulation pulses,in addition to the total treatment time. Additionally, while sequences1401, 1402, 1304, and 1405 ablate the entire target volume in a single“pass” of the bubble cloud across the target volume, sequence 1403ablates the target volume with two “passes” of the bubble cloud.Comparing sequence 1404 to 1405, both sequences have a therapy PRF of150 Hz, a bubble manipulation PRF of 600 Hz, and a total treatment timeof 48 minutes, however sequence 1403 completes two “passes” of thebubble cloud across the target tissue volume, at 24 minutes per pass,compared to a single 48 minute “pass” in sequence 1404.

FIG. 14A illustrate the temperature profiles of the sequence strategiesof Table 1, and FIG. 14B illustrate the resulting t43 curves producedduring treatment. The lowest temperature rises are observed for thesequences that utilize the lowest therapy PRFs (1403 and 1404). Amongstthese two, there is some thermal advantage to making multiple fasterpasses through the volume (sequence 1403 uses two 24 minute passes) incomparison to a single slower pass (sequence 1404 uses one 48 minutepass). The former strategy is likely to provide benefit by virtue of thefact that it allows for effective distribution of the incident acousticenergy in time and space. Rather than dwelling in any given location foran extended time, the enhanced motion of the transducer allows for oneregion of the volume to cool as another is being heated.

Sequences 1401 and 1402 have been observed to produce prefocal body wallinjury during in-vivo liver treatment. Unsurprisingly, these sequencesgenerate the greatest temperature rises of those illustrated.

The type of volume treatment path employed by the histotripsy systemsdescribed herein can also have implications on the thermal effect intissue. As described above, some of the potential treatment patternsinclude the “Standard Z” (SZ) pattern, the “Top-Down” pattern, the“Bottom-Up” pattern, the “Standard Z Side-Side” pattern, the “Standard ZShuffle” pattern, and the “Spiral In-Out” pattern.

TABLE 2 Cooling Step Therapy Cooling Imple- Total % On- TreatmentPattern On-Time Time mentation Time Time No SZ 25:50 00:00 N/A 25:50 100% Cooling Cooling SZ 25:50 24:00 Following 49:50 51.8% Scheme 1Groups of Points Cooling SZ 25:50 24:00 Point-by- 49:50 51.8% Scheme 2Point Cooling SZ 25:50 12:55 Point-by- 38:45 66.7% Scheme 3 PointCooling SZ 25:50 51:40 Point-by- 1:17:30 33.3% Scheme 4 Point

Table 2 illustrates various cooling techniques performed with the SZpattern. The SZ pattern without the incorporation of cooling stepsserved as the control. Cooling Schemes 1 and 2 both incorporated 24minutes of total cooling. In Scheme 1 this cooling time was divided into24 1-minute cooling steps, equally distributed throughout the treatmentafter a fixed number of treatment points. Conversely, in Scheme 2 the 24minutes of cooling time was equally distributed after each treatmentpoint. In these cases the incorporation of 24 minutes of coolingresulted in a percent on-time of 51.8%. Schemes 3 and 4 explore theinfluence of the therapy on-time:cooling-time ratio, with percenton-times of 66.7% and 33.3%, respectively. In both of these cases thecooling steps are equally distributed following each treatment point.

One of the advantageous features of the “DZ” treatment pattern is thefact that it provides logical points at which to implement coolingsteps, such as a cooling time period. The alternating column (andanalogously, alternating slices) approach allows for cooling stepsduring the motion time between the columns (and slices). In effect, thepattern has inefficiencies purposely built-in in order to accommodatestrategically placed cooling times.

TABLE 3 Therapy Elec- Treat- On- Cooling Total tronic Power ment TimeTime Time % On- Steering Supply Scheme Pattern (min) (min) (min) Time(cm) Setting 1 SZ 31 0 31 100% 0 50% 2 DZ, 31 0 31 100% 0 50% Bottom- Up3 DZ, 31 13.5 44.5 70% 0 50% Bottom- Up 4 DZ, 31 45.5 76.5 41% 0 50%Bottom- Up 5 SZ 31 0 31 100% −1 50% 6 SZ 31 0 31 100% −2 61%

Treatment schemes 3 and 4 in Table 3 above describe two varieties ofimplementing cooling steps into the DZ pattern. In Scheme 3 therapy ishalted only during the motor motion between columns, which isanticipated to be the minimum cooling time implemented in the DZsequence. In Scheme 4 additional cooling time is imposed beyond the timerequired for motor motion; this scheme was selected such as to givepreliminary insight regarding the relationship between the temperatureprofile and the percent on-time of the volume treatment. It should benoted that Scheme 2, in which therapy was delivered over the entiremotion path (including motions between columns), is not the intendedimplementation of the DZ pattern. Rather, this scheme is included solelyto compare the thermal properties of the path to those of the SZ path.

The thermal profiles resulting from the five treatment schemes used toinvestigate the implementation of cooling steps during volume treatmentare displayed in FIGS. 15A-15B. No cooling is shown in plot 1501, andcooling schemes 1-4 from Table 2 are illustrated as plots 1502-1505,respectively. As expected, the treatment conducted without theimplementation of cooling (i.e. 100% on-time) produced the highesttemperature rise (Δt=12.7° C.). When cooling was implemented followingeach treatment point a reduction in temperature rise was observed, withvolume treatments having percent on-times of 66.7% (Cooling Scheme1504), 51.8% (Cooling Scheme 1503), and 33.3% (Cooling Scheme 1505)producing temperature rises of 10.5, 8.3, and 6.2° C., respectively.

Although an increased rate of pulse delivery is typically associatedwith increased thermal deposition, the decreased cavitation thresholdassociated with high PRF may act to offset this in such a way as to leadto lower overall temperature rises. Thus, the present disclosure alsoprovides pulse sequences with relatively high PRFs that can be used toreduce thermal deposition in tissue.

TABLE 4 Total Power Treatment Dose Time % On- Supply Scheme SequencePattern (Pulses/Point) (min) Time Setting 1 1601 SZ 943 25:50 100% 50%(Average) 2 1602 DZ, 947 43:30 60% 50% Top-Down 3 1603 DZC, 947 32:00 41% 42% Top-Down

FIGS. 16A-16B illustrate the thermal effect of high-PRF sequences withcooling times. Using the 1601 sequence with the SZ pattern produced atemperature rise of 21.2° C., whereas 1602 sequence with the top-downvariant of the DZ pattern generated a temperature rise of 12.9° C. Thecorresponding t43 traces peaked at 1.43×10⁵ and 1.21×10³ equivalentminutes, respectively.

The implementation of sequence 1603 in the top-down variant of the DZCpattern produced further reduction in thermal deposition, with atemperature rise of only 6.2° C. and peak t43 of 9.6 equivalent minutes.As such, it appears that the high-PRF strategy is extremely promisingfor reducing prefocal thermal effects. On first pass increasing thepulse rate as a means of reducing thermal deposition may seemcounterintuitive, as temperature rise scales linearly with the rate ofpulse application at a given amplitude. However, the decreased bubblecloud initiation threshold associated with higher PRFs appears tosignificantly outweigh this effect. This is the result of the fact thattemperature increase scales with the square of the pulse amplitude; assuch, if the threshold amplitude discrepancy is great enough, thethermal benefit of lower pressure will dominate over the thermaldrawback of increased pulse rate.

In addition to the apparent thermal benefits, there is a second majoradvantage of increased therapy PRF: a reduction in treatment time. Thisis illustrated by Schemes 2 and 3, which both used (essentially) thesame pattern with the same amount of cooling time (cooling only duringinter-column motions). In this case delivering a dose of 947pulses/point required a total treatment time of 43:30 with sequence1602; delivering the same dose with sequence 1603 required only 32:00.

Treatment Planning

Systems and methods are further described herein that include agraphical user interface (GUI) used to plan and carry out ablationtherapies. Referring to FIGS. 17A-17E, a GUI of the present disclosurecan include one or more internal views of a patient, including a targettissue volume. An operator (such as a physician) can identify the targettissue volume in the real-time imaging and mark both the target tissuevolume and a desired margin around the target tissue volume in thesystem. The system can automatically calculate/determine the size of thetarget tissue volume from the selection, as well as calculate plannedtreatment time for a specific set of treatment parameters for userdefined targets and regions of interest. Referring to FIG. 17B, the GUIcan overlay on top of the target tissue volume a chosen treatment planand pattern, including configurable views of treatment and bubble cloudlocations and spacing, which can be preselected, or user selected, fromany of the treatment patterns described above (e.g., SZ pattern, DZpattern, etc).

In some embodiments, the depth of the target tissue volume can be afactor in determining which pulse sequence parameters and/or treatmentpatterns to use, and/or part of the treatment algorithm, including aspart, and an input to an embedded treatability matrix or look up table.Thus, the GUI can further enable the user to measure the depth of thetarget treatment volume, as shown in FIG. 17C.

FIG. 17D illustrates one example of a Therapy:Cooling TreatabilityMatrix or look-up table, which can be used during therapy to determinethe appropriate treatment and cooling parameters to prevent or reducethermal injury to non-targeted tissue sites. In some examples, thehistotripsy system can automatically use the depth of the target tissueand the selected drive voltage % to determine optimal pulse parameters,including the ratio of treatment pulses to cooling time, that will avoidtissue damage to non-targeted tissues. This implementation thereforeadvantageously eliminates or reduces the risk of, for example, damage orheating to pre-focal tissues located between the target tissue and thetherapy transducer.

The Therapy:Cooling Treatability Matrix uses the selected drive voltage(%) and the target tissue depth (in cm) to automatically determine theratio of therapy to cooling time during a given treatment session. Asdescribed above, a 1:1 ratio of therapy to cooling will have equalamounts of time during a treatment session dedicated to therapy pulsedelivery and to cooling periods (periods in which no therapy isdelivered). For example, if the therapy total treatment time is 30minutes and the therapy:cooling ratio is 1:1, then 15 minutes of thetotal treatment time will be spent delivering therapy pulses to tissue,and 15 minutes of the total treatment time will be spent delivering notherapy pulses to tissue (e.g., repositioning the therapy transducer fordelivery of subsequent bubble clouds).

Referring back to the treatability matrix of FIG. 17D, the drive voltageand target tissue depth are used to determine the ratio of therapy tocooling to avoid non-targeted tissue damage. For drive voltage andtarget tissue depth combinations falling in the region between line 1701and the x-axis of FIG. 17D, a first cooling ratio can be applied to thetherapy pulse sequence to avoid unwanted tissue damage. In one example,the first cooling ratio can comprise a 1:1 ratio of therapy to cooling(e.g., for a given treatment time, therapy is delivered 50% of thetreatment time and cooling, or no therapy, is applied 50% of thetreatment time). For drive voltage and target tissue depth combinationsfalling in the region between line 1701 and line 1702, a second coolingratio can be applied to the therapy pulse sequence to avoid unwantedtissue damage. In one example, the second cooling ratio can comprise a1:2 ratio of therapy to cooling (e.g., for a given treatment time,therapy is delivered 33% of the treatment time and cooling, or notherapy, is applied 67% of the treatment time). For drive voltage andtarget tissue depth combinations falling in the region between line 1702and line 1703, a third cooling ratio can be applied to the therapy pulsesequence to avoid unwanted tissue damage. In one example, the thirdcooling ratio can comprise a 1:3 ratio of therapy to cooling (e.g., fora given treatment time, therapy is delivered 25% of the treatment timeand cooling, or no therapy, is applied 75% of the treatment time). Fordrive voltage and target tissue depth combinations falling in the regionbetween line 1703 and line 1704, a fourth cooling ratio can be appliedto the therapy pulse sequence to avoid unwanted tissue damage. In oneexample, the fourth cooling ratio can comprise a 1:4 ratio of therapy tocooling (e.g., for a given treatment time, therapy is delivered 20% ofthe treatment time and cooling, or no therapy, is applied 80% of thetreatment time). For drive voltage and target tissue depth combinationsfalling in the region between line 1704 and line 1705, a fifth coolingratio can be applied to the therapy pulse sequence to avoid unwantedtissue damage. In one example, the fifth cooling ratio can comprise a1:5 ratio of therapy to cooling (e.g., for a given treatment time,therapy is delivered 16% of the treatment time and cooling, or notherapy, is applied 84% of the treatment time). It should be understoodthat the exact cooling ratios described herein as examples can beadjusted depending on the target tissue type, total treatment time,transducer type, driving amplifier, target tissue size, depth, etc.

Referring to FIG. 17E, the real-time imaging can be used to guide theuser during the therapy itself. For example, in one embodiment, the usercan be instructed to increase the driving voltage of the therapytransducer(s) until a bubble cloud appears in the real-time imaging. Thebubble cloud or cavitation will appear in the tissue when the drivingvoltage achieves the cavitation threshold required of the selectedtarget tissue location. This may further include guiding a user througha test pulse protocol to inform a patient/target specific treatment planthat accounts for the combination of, but not limited to, sequence,pattern, pathway and any intervening tissue/blockage, to ensure robusttissue effect and minimal and/or no collateral damage to adjacent orintervening tissue.

Use Environments

The disclosed system, methods of use, and use of the system, may beconducted in a plethora of environments and settings, with or withoutvarious support systems such as anesthesia, including but not limitedto, procedure suites, operating rooms, hybrid rooms, in and out-patientsettings, ambulatory settings, imaging centers, radiology, radiationtherapy, oncology, surgical and/or any medical center, as well asphysician offices, mobile healthcare centers or systems, automobiles andrelated vehicles (e.g., van), and/or any structure capable of providingtemporary procedure support (e.g., tent). In some cases, systems and/orsub-systems disclosed herein may also be provided as integrated featuresinto other environments, for example, the direct integration of thehistotripsy Therapy sub-system into a MRI scanner or patientsurface/bed, wherein at a minimum the therapy generator and transducerare integral to such, and in other cases wherein the histotripsyconfiguration further includes a robotic positioning system, which alsomay be integral to a scanner or bed centered design.

1. A histotripsy treatment method, comprising the steps of: receiving adigital treatment plan that includes a target tissue volume of a subjectdivided into a plurality of treatment volumes arranged within aplurality of radial layers; moving a focus of an ultrasound therapytransducer array to a first of the plurality of treatment volumes withina first radial layer of the plurality of radial layers; forming acavitation bubble cloud in the first of the plurality of treatmentvolumes with the ultrasound therapy transducer array; moving the focusin a spiraling fashion and forming a cavitation bubble cloud through theremaining plurality of treatment volumes in the first radial layer;transitioning from the first radial layer to a second radial layer ofthe plurality of radial layers; moving the focus in a spiraling fashionand forming a cavitation bubble cloud through the remaining plurality oftreatment volumes in the second radial layer; and repeating the moving,forming, and transitioning steps for each of a remaining plurality ofradial layers.
 2. The method of claim 1, wherein the target tissuevolume is generally spherical.
 3. The method of claim 1, wherein thetarget tissue volume is contoured to a tumor.
 4. The method of claim 1,wherein the target tissue volume includes a margin.
 5. The method ofclaim 1, wherein the target tissue volume is an ellipsoid.
 6. The methodof claim 1, wherein moving the focus further comprises mechanicallymoving the focus with a robotic positioning system that is coupled tothe ultrasound therapy transducer array.
 7. The method of claim 1,wherein moving the focus further comprises electronically steering thefocus with the ultrasound therapy transducer.
 8. The method of claim 1,wherein the plurality of treatment volumes are column-shaped.
 9. Themethod of claim 1, further comprising electronically steering the focusat each of the plurality of treatment volumes before moving the focus tosubsequent treatment volumes.
 10. The method of claim 9, whereinelectronically steering the cavitation bubble cloud further compriseselectronically steering the cavitation bubble cloud in a z-directionthrough each of the plurality of treatment volumes.
 11. The method ofclaim 1, wherein the first radial layer is centrally located within thetarget tissue volume.
 12. The method of claim 1, wherein the digitaltreatment plan progresses through the plurality of radial layers from acentral-most radial layer to an outer-most radial layer.
 13. The methodof claim 1, wherein moving the focus in a spiraling fashion comprisesmoving the focus outward in a spiraling fashion.
 14. The method of claim1, wherein transitioning from the first radial layer to the secondradial layer comprises moving the focus to a closest untreated treatmentvolume of the plurality of treatment volumes of the second radial layer.15. The method of claim 1, wherein the plurality of treatment volumescover at least 90% of the target tissue volume.
 16. An ultrasoundtherapy system, comprising; a robotic positioning system; an ultrasoundtherapy transducer array connected to the robotic positioning system; agenerator operatively coupled to the ultrasound therapy transducerarray, the generator and ultrasound therapy transducer array beingconfigured to deliver histotripsy pulses into a subject to generate acavitation bubble cloud in the subject; at least one processoroperatively coupled to the robotic positioning system and the generator,the at least one processor being configured to control the roboticpositioning system and the generator to provide histotripsy therapy tothe subject according to a treatment plan that includes a target tissuevolume divided into a plurality of treatment volumes arranged within aplurality of radial layers by: controlling the robotic positioningsystem to move a focus of an ultrasound therapy transducer array to afirst of the plurality of treatment volumes within a first radial layerof the plurality of radial layers; controlling the generator to deliverhistotripsy pulses with the ultrasound therapy transducer array to forma cavitation bubble cloud in the first of the plurality of treatmentvolumes with the ultrasound therapy transducer array; controlling therobotic positioning system and the generator to move the focus in aspiraling fashion and form cavitation bubble clouds through theremaining plurality of treatment volumes in the first radial layer;controlling the robotic positioning system to transition from the firstradial layer to a second radial layer of the plurality of radial layers;moving the focus in a spiraling fashion and forming a cavitation bubblecloud through the remaining plurality of treatment volumes in the secondradial layer; and repeating controlling the robotic positioning systemand the generator to move the focus and deliver histotripsy pulses foreach of a remaining plurality of radial layers.
 17. The ultrasoundtherapy system of claim 16, further comprising an imaging systemconfigured to image the cavitation bubble cloud in real-time.
 18. Theultrasound therapy system of claim 16, wherein the ultrasound therapysystem is configured to communicate with an imaging system selected fromthe group consisting of MRI, CT, cone beam CT (CBCT), PET-CT, and/or anultrasound imaging system.
 19. The ultrasound therapy system of claim18, wherein the treatment plan is based on pre-treatment images.
 20. Theultrasound therapy system of claim 17, wherein the imaging systemcomprises an ultrasound imaging probe configured within a bore of theultrasound therapy transducer array.
 21. The ultrasound therapy systemof claim 16, wherein the at least one processor receives the treatmentplan.
 22. The ultrasound therapy system of claim 16, wherein the atleast one processor is configured to generate the treatment plan. 23.The ultrasound therapy system of claim 16, wherein the target tissuevolume of the treatment plan has a shape selected from the groupconsisting of generally spherical, an ellipsoid, and an arbitrary shape.24. The ultrasound therapy system of claim 16, wherein the at least oneprocessor is configured to control the robotic positioning system toprogress through the plurality of radial layers from a distal-mostradial layer to a proximal-most radial layer.
 25. The ultrasound therapysystem of claim 16, wherein the plurality of treatment volumes arecolumn-shaped.
 26. The ultrasound therapy system of claim 16, whereinmoving the focus in a spiraling fashion comprises moving the focusoutward in a spiraling fashion.
 27. The ultrasound therapy system ofclaim 16, wherein controlling the robotic positioning system totransition from the first radial layer to the second radial layercomprises moving the focus to a closest untreated treatment volume ofthe plurality of treatment volumes of the second radial layer.